KR20040004412A - Spiro-pyrimidine-2,4,6-trione Metalloproteinase Inhibitors - Google Patents

Abstract

The present invention relates to 5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors of formula (I) and to pharmaceutical compositions and methods for the treatment of inflammation, cancer and other diseases.

<Formula I>

In the formula, "A" is a 5-7 membered heterocyclic ring as defined in the specification.

Description

Spiro-pyrimidine-2,4,6-trione Metalloproteinase Inhibitors

The present invention relates to 5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors, and to pharmaceutical compositions and methods for the treatment of inflammation, cancer and other diseases.

The compounds of the invention are inhibitors of zinc metalloendopeptidase, in particular metalloendopeptidase belonging to the matrix metalloproteinases (also called MMP or matrixin).

MMP subfamily enzymes currently have 17 members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). MMPs are best known for regulating the conversion of extracellular matrix proteins and play an important role in normal physiological processes such as reproduction, development and differentiation. In addition, MMPs are expressed in several pathological situations where abnormal connective tissue turnover occurs. For example, MMP-13, an enzyme with potent activity in the degradation of type II collagen (major collagen in cartilage), has been demonstrated to be overexpressed in osteoarticular cartilage (Mitchell, et al., J. Clin. Invest. , 97, 761 (1996)]. Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarticular cartilage, and inhibition of some or all of these MMPs is common in joint diseases such as osteoarthritis or rheumatoid arthritis. It is expected to slow down or block the promotion of phosphorus cartilage loss.

It is known that different combinations of MMPs are expressed in different pathological situations. Thus, inhibitors with specific selectivity for individual MMPs may be preferred for each disease.

Matrix metalloproteinase inhibitors are well known in the literature. Hydroxamic acid MMP inhibitors are exemplified in European Patent Publication No. 606,046, published July 13, 1994. Several pyrimidine-2,4,6-trione MMP inhibitors are described in PCT Publication WO 98/58925, published December 30, 1998. PCT Publication WO 00/47565, published August 17, 2000, describes certain aryl substituted pyrimidine-2,4,6-trione MMP inhibitors. US Provisional Application No. 09/635156, filed August 9, 2000 (claimed priority US Provisional Application No. 60/148547, filed August 12, 1999), is a heteroaryl substituted pyrimidine-2,4,6 -Trion MMP inhibitors are described. A U.S. provisional application entitled "pyrimidine-2,4,6-trione metalloproteinase inhibitors" filed October 26, 2000, describes certain pyrimidine-2,4,6-trions. . Barbituric acid and methods for its preparation are well known in the literature, see for example Goodman and Gilman's, "The Phamacological Basis of Therapeutics," 345-382 (Eighth Edition, McGraw Hill, 1990). . Each publication and application cited above is hereby incorporated by reference in its entirety.

<Overview of invention>

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Wherein "A" is a 5-7 membered heterocyclic ring selected from the group consisting of

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are hydrogen, (C _1- C ₄ ) alkyl, (C ₁ -C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) Cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl, each independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C _1- C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl are halo, (C ₁ -C ₄ ) alkyl, on a ring carbon atom which may form additional bonds, Optionally substituted 1 to 3 times per ring by a substituent independently selected from (C ₁ -C ₄ ) alkoxy, —CN, —OH and —NH ₂ ;

X is (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₁₀ ) heteroaryl;

Y is a bond, oxygen, sulfur,> C = O,> SO ₂ ,> S = O, -CH _2- , -CH ₂ O-, -O (CH ₂ ) _n- , -CH ₂ S-, -S (CH ₂ ) _n- , -CH ₂ SO-, -CH ₂ SO _2- , -SO (CH ₂ ) _n- , -SO ₂ (CH ₂ ) _n- , -NR ¹⁴ , -NR ¹⁴ (CH ₂ ) _n- , -CH ₂ [N (R ¹⁴ )]-, -CH ₂ (CH ₂ ) _n- , -CH = CH-, -C≡C-,-[N (R ¹⁴ )]-SO ₂ -and -S0 ₂ [N (R ¹⁴ )]-is selected from the group consisting of;

n is an integer from 1 to 4;

R ¹⁴ is hydrogen or (C ₁ -C ₄ ) alkyl;

Z is selected from the group consisting of (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heterocyclyl and (C ₁ -C ₁₀ ) heteroaryl , One or two carbon-carbon single bonds of (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₁₀ ) heterocyclyl may be optionally replaced with a carbon-carbon double bond,

Each of X or Z is independently F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl on a ring carbon atom capable of forming additional bonds Optionally substituted one or two times per ring by a substituent independently selected from (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy ;

G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , where G is a substituent on a ring carbon atom of Z that can form additional bonds, excluding the alpha position relative to the point of attachment of the Z ring and Y Oriented in position;

p is an integer from 0 to 4;

R ¹⁵ is halo, —CN, —NO ₂ , OH, (C ₁ -C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₁ -C ₄ ) perfluoroalkyl, perfluoro ( C ₁ -C ₄ ) alkoxy, R ^18- , R ¹⁸ -O-, R ^18- (C ₁ -C ₄ ) alkyl-O-, R ^18- (C = O)-, R ^18- (C = O ) -O-, R ¹⁸ -O- (C = O)-, R ¹⁸ -S-, R ^22- (S = O)-, R ^18- (SO ₂ )-, R ^22- (SO ₂ )- (NR ²¹ )-, R ^19- (C = O)-(NR ²¹ )-, R ²² -O- (C = O)-(NR ²¹ )-, (R ¹⁹ R ²⁰ ) N-, (R ¹⁹ R ²⁰ ) N- (SO ₂ )-, (R ¹⁹ R ²⁰ ) N- (C = O)-, (R ¹⁹ R ²⁰ ) N- (C = O)-(NR ²¹ )-and (R ¹⁹ R ²⁰ ) N- (C═O) —O— is independently selected from the group consisting of;

Each of R ¹⁶ and R ¹⁷ is independently selected from hydrogen and (C ₁ -C ₄ ) alkyl, or

Or R ¹⁶ and R ¹⁷ can optionally form a 5 to 10 membered carbocyclic ring with the carbon atom to which they are attached;

R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are hydrogen, (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) hetero Independently selected from the group consisting of aryl and (C ₁ -C ₁₀ ) heterocyclyl, wherein (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) Heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C _1- ) on ring carbon atoms that can form additional bonds C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) Alkyl] may be optionally substituted 1 to 3 per ring by a substituent independently selected from ₂ -N- and (C ₃ -C ₈ ) cycloalkyloxy, wherein the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀₎ heterocyclyl moieties may also be optionally substituted by oxo, it said (C ₁ -C ₁₀₎ heteroaryl and (C ₁ -C ₁₀₎ heterocyclyl residues are weight On ring nitrogen atoms which may have a substituent (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ alkyl - (C = O) - 1 to 2 times per ring by substituents independently selected from the group consisting of May be optionally substituted;

Or R ¹⁹ and R ²⁰ may optionally form a 3-8 membered heterocyclic ring with the nitrogen to which they are attached;

Or R ¹⁹ and R ²¹ may optionally form a 3-8 membered heterocyclic ring with the nitrogen, carbon or oxygen to which they are attached;

R ²² is (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocycle It is selected from the group consisting of, wherein said (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties on ring carbon atoms capable of forming an additive combination of F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C ₁ -C ₄₎ perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈ ) may be optionally substituted 1 to 3 per ring by a substituent independently selected from cycloalkyloxy, wherein the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl moiety are also present in oxo by optionally may be substituted, the (C ₁ -C ₁₀₎ heteroaryl and (C ₁ -C ₁₀₎ heterocyclyl residues are ring which may be further have a substituent group (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ alkyl on the atom - (C = O) - group may be independently substituted one to two times per ring which are selected from the substituents consisting of or;

Alternatively, R ²¹ and R ²² may optionally form a 3-8 membered heterocyclic ring with the nitrogen, oxygen or sulfur to which they are attached.

The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (I). The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the invention mentioned above are non-toxic acid addition salts, ie pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, Sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sacrate, benzoate, methanesulfo Acids forming salts containing nates, ethanesulfonates, benzenesulfonates, p-toluenesulfonic acid and palmoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] to be.

The invention also relates to base addition salts of formula (I). Chemical bases which can be used as reagents to prepare pharmaceutically acceptable base salts of compounds of formula (I) which are originally acidic are those which form non-toxic base salts with said compounds. Such non-toxic base salts include salts derived from pharmacologically acceptable cations such as alkali metal cations (eg potassium and sodium) and alkaline earth metal cations (eg calcium and magnesium), ammonium or water soluble amine addition salts such as N-methylglu Carmine (meglumine), and other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines are included.

The term “bond” as used herein for the Y group means that the X and Z groups are directly linked through a carbon-carbon bond to form a pendant aryl ring such as diphenyl.

The dashed line used for each heterocyclic ring “A” of formula a), b), c), g), h), i), k) and l) represents an optional double bond. The exact position of the optional double bond for each heterocyclic ring “A” of formula a), b), c), g), h), i), k) and l) is as defined in the specification. Whenever the dotted line spans two carbon atoms, the two carbon atoms are tetravalent and the remaining substituent (s) (ie, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ It will be appreciated by those skilled in the art that any of R ¹⁰ , R ¹¹ , R ¹² or R ¹³ ) may be absent.

The term "alkyl" as used herein, unless stated otherwise, includes saturated monovalent hydrocarbon radicals having straight chain, branched moieties, or combinations thereof. The alkyl group may be optionally substituted wherever present by a suitable substituent.

The term "alkenyl" as used herein, unless stated otherwise, includes hydrocarbon radicals containing one or more olefinic linkages and having straight, branched or cyclic moieties or combinations thereof.

The term "alkynyl" as used herein, unless stated otherwise, includes hydrocarbon radicals that contain one or more carbon-carbon triple bond linkages and have straight, branched or cyclic moieties or combinations thereof.

The term "cycloalkyl", as used herein, unless otherwise stated, optionally contains 1 to 2 double bonds and optionally 1 to 3 suitable substituents as defined below, such as fluoro, chloro, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, (C ₆ -C ₁₀ ) aryloxy, trifluoromethoxy, difluoromethoxy or (C ₁ -C ₄ ) alkyl, more preferably fluoro, chloro, methyl, ethyl and meth Mono or bicyclic carbocyclic rings substituted with oxy (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo [2.2.1 ] Heptanyl, bicyclo [3.2.1] octanyl and bicyclo [5.2.0] nonanyl, and the like).

The term "alkoxy" as used herein includes O-alkyl groups, wherein "alkyl" is as defined above.

The term "halo" as used herein, unless stated otherwise, includes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term "aryl" as used herein, unless stated otherwise, includes organic radicals derived from aromatic hydrocarbons by one or more hydrogen removal, such as phenyl, naphthyl, indanyl or tetrahydronaphthyl, which include 1 to 3 Suitable substituents such as fluoro, chloro, cyano, nitro, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryloxy, (C ₃ -C ₈ ) cycloalkyloxy, tri Optionally substituted with fluoromethoxy, difluoromethoxy, or (C ₁ -C ₆ ) alkyl.

The term "heteroaryl" as used herein, unless otherwise stated, refers to organic radicals derived from aromatic heterocyclic compounds by one or more hydrogen removal, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1- Benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnaolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl , Indolinyl, indolyl, 3H-indolyl, isoindoleyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pterridinyl, fury Nil, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and include triazolyl, and this time, the (C ₁ -C ₁₀₎ Interrogating aryl with one or two suitable substituents on the ring carbon atoms capable of forming an additional bond, for example F, Cl, Br, CN, OH, (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ Purple Optionally substituted with fluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy. The groups may be C-attached or N-attached if possible. For example, the pyrrolyl group can be pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached).

The term "heterocyclyl" as used herein, unless otherwise stated, refers to organic radicals derived from non-aromatic heterocyclic compounds by one or more hydrogen removal, such as 3-azabicyclo [3.1.0] hexanyl, 3-azabi Cyclo [4.1.0] -heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-ditianyl, hexahydro Azepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, Pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl , Tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl and tritianyl. The groups may be C-attached or N-attached if possible. For example, piperidinyl may be piperidin-1-yl (N-attached) or piperidin-3-yl (C-attached). Such groups derived from the compounds listed above may, where possible, suitable substituents such as oxo, F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, ( Optionally substituted with C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy.

The phrase “suitable substituents” means chemically and pharmaceutically acceptable functional groups, ie, moieties that do not interfere with the inhibitory activity of the compounds of the invention. Such suitable substituents can be readily selected by those skilled in the art. Specific examples of suitable substituents include halo group, perfluoroalkyl group, perfluoroalkoxy group, alkyl group, hydroxy group, oxo group, mercapto group, alkylthio group, alkoxy group, aryl or heteroaryl group, aryloxy or heteroaryloxy group , Aralkyl or heteroaralkyl group, aralkoxy or heteroaralkoxy group, carboxyl group, amino group, alkyl- and dialkylamino group, carbamoyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, arylcarbonyl group, aryl Oxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, and the like, but are not limited thereto.

Unless stated otherwise, the phrase "without the alpha position with respect to the attachment point of the Z ring and Y" refers to the bond linkage of Z and G (ZG bond) to the bond linkage of Y and Z (YZ bond). It means chemically and pharmaceutically acceptable orientation. This relative orientation can be meta if the Z-G bond is 1,3 position relative to the Y-Z bond. Another relative orientation may be para when the Z-G bond is 1,4 position relative to the Y-Z bond.

Some compounds of formula (I) contain chiral centers and therefore exist in different enantiomeric forms. The present invention includes all optical isomers, enantiomers, diastereomers and stereoisomers of the compounds of formula (I), and mixtures thereof. The compounds of the present invention also exist in different tautomeric forms. The present invention relates to all tautomers of the compounds of formula (I). Those skilled in the art will appreciate that the pyrimidine-2,4,6-trione nucleus exists as a mixture of tautomers in solution. The various ratios of the solid and liquid forms of the tautomers depend on the various substituents on the molecule as well as the particular crystallization technique used to isolate the compound.

In an embodiment of the invention, the heterocyclic ring “A” of the compound of formula I is selected from formula a) or b):

Wherein X is (C ₆ -C ₁₀ ) aryl, preferably phenyl. In this embodiment, Y is a bond, oxygen,> C = O, -CH _2- , -CH ₂ 0-, -O (CH ₂ ) _n- , -CH ₂ CH _2- , -CH = CH- and- Is selected from the group consisting of C≡C-, wherein n is 1 or 2, preferably Y is selected from the group consisting of oxygen, -OCH ₂ -and -CH ₂ 0-, more preferably Y Is oxygen.

In another embodiment of the invention, heterocyclic ring “A” has formula a) or b) where X is (C ₆ -C ₁₀ ) aryl, preferably phenyl. In this embodiment, Y is sulfur,> S0 ₂ ,> S = O, -CH ₂ S-, -S (CH ₂ ) _n , -CH ₂ SO-, -CH ₂ SO _2- , -SOCH ₂ -and -SO ₂ (CH ₂ ) _n- , wherein n is 1 or 2, preferably Y is sulfur or> SO ₂ .

In another embodiment of the invention, heterocyclic ring “A” has formula a) or b) where X is (C ₆ -C ₁₀ ) aryl, preferably phenyl. In this embodiment, Y is ^{_{CH 2 [N (R 14)}} ] -,> NR 14, -NR 14 (CH 2) n -, -SO 2 [N (R 14)] - and - [N (R ¹⁴ )]-SO _2- , wherein R ¹⁴ is hydrogen or methyl and n is 1 or 2.

In another embodiment of the invention, heterocyclic ring “A” is a compound wherein X is benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzo Thiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, iso Indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxdiazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl (C ₁ -C ₁₀ ) selected from the group consisting of nil, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl Heteroaryl, wherein the (C ₁ -C ₁₀ ) heteroaryl can form additional bonds F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C) ₄ ) optionally substituted with one or two substituents independently selected from alkoxy and (C ₃ -C ₈ ) cycloalkyloxy, preferably X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxa Is selected from the group consisting of zolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, most preferably Or a) or b) wherein X is pyridinyl. In this embodiment, Y is a bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -or -CH ₂ O-, preferably Y is oxygen, -OCH ₂ -or -CH ₂ 0 -, More preferably Y is oxygen.

In another embodiment of the invention, heterocyclic ring “A” is a compound wherein X is benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzo Thiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, iso Indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxdiazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl (C ₁ -C ₁₀ ) selected from the group consisting of nil, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl Heteroaryl, wherein the (C ₁ -C ₁₀ ) heteroaryl can form additional bonds F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C) ₄ ) optionally substituted with one or two substituents independently selected from alkoxy and (C ₃ -C ₈ ) cycloalkyloxy, preferably X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxa Is selected from the group consisting of zolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, most preferably Or a) or b) wherein X is pyridinyl. In this embodiment, Y is sulfur,> SO ₂ ,> S = O, -CH ₂ S-, -S (CH ₂ ) _n- , -CH ₂ SO-, -CH ₂ SO _2- , -SO ₂ CH ₂ -and -SO ₂ (CH ₂ ) _n- , wherein n is 1 or 2, preferably Y is sulfur or> SO ₂ .

In another embodiment of the invention, heterocyclic ring “A” is a compound wherein X is benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzo Thiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, iso Indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxdiazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl (C ₁ -C ₁₀ ) selected from the group consisting of nil, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl Heteroaryl, wherein the (C ₁ -C ₁₀ ) heteroaryl can form additional bonds F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C) ₄ ) optionally substituted with one or two substituents independently selected from alkoxy and (C ₃ -C ₈ ) cycloalkyloxy, preferably X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxa Is selected from the group consisting of zolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, most preferably Or a) or b) wherein X is pyridinyl. In this embodiment Y is CH ₂ [N (R ¹⁴ )]-,> NR ¹⁴ , -NR ¹⁴ (CH ₂ ) _n- , -S0 ₂ [N (R ¹⁴ )]-, and-[N (R ¹⁴ ) ] -SO _2- , wherein R ¹⁴ is hydrogen or methyl and n is 1 or 2.

In another embodiment of the invention, heterocyclic ring “A” is a compound wherein X is benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzo Thiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, iso Indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxdiazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl (C ₁ -C ₁₀ ) selected from the group consisting of nil, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl Heteroaryl, wherein the (C ₁ -C ₁₀ ) heteroaryl can form additional bonds F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C) ₄ ) optionally substituted with one or two substituents independently selected from alkoxy and (C ₃ -C ₈ ) cycloalkyloxy, preferably X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxa Is selected from the group consisting of zolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, most preferably Has the formula a) wherein X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ 0-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula a) as defined in the paragraph above wherein the dashed line is a double bond.

In another embodiment of the invention, heterocyclic ring “A” is a compound wherein X is benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzo Thiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, iso Indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxdiazolyl, oxazolyl, phthalazinyl, pterridinyl, furinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl (C ₁ -C ₁₀ ) selected from the group consisting of nil, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl Heteroaryl, wherein the (C ₁ -C ₁₀ ) heteroaryl can form additional bonds F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C) ₄ ) optionally substituted with one or two substituents independently selected from alkoxy and (C ₃ -C ₈ ) cycloalkyloxy, preferably X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxa Is selected from the group consisting of zolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, most preferably Has the formula b) wherein X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, heterocyclic ring “A” has formula b) as defined in the paragraph above wherein the dashed line is a double bond.

In another embodiment of the invention, the heterocyclic ring “A” has the formula c):

c)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring "A" has formula c) in which the dashed line is a double bond, so that the heterocyclic ring "A" of formula c) is represented by the formulas c ₁ ) and c ₂ ) Is selected from the group consisting of:

In another embodiment of the invention, the heterocyclic ring “A” has the formula d):

d)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ 0-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula e):

e)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> S0 ₂ , -OCH ₂ -and -CH ₂ 0-, preferably Y is oxygen, -OCH _2- Or -CH ₂ 0-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula f):

f)

Wherein X is imidazolyl, isothiazolyl, isoxazolyl, oxdiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; Preferably X is (C ₁ -C ₁₀ ) heteroaryl selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula g):

g)

Wherein X is imidazolyl, isothiazolyl, isoxazolyl, oxdiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; Preferably X is (C ₁ -C ₁₀ ) heteroaryl selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ 0-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula g) as defined in the paragraph above wherein the dashed line is a double bond.

In another embodiment of the invention, the heterocyclic ring “A” has the formula h):

h)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, heterocyclic ring “A” has the formula h) as defined in the paragraph above wherein the dashed line is a double bond.

In another embodiment of the invention, the heterocyclic ring “A” has formula i):

i)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyridinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has formula i) in which the dotted line is a double bond, so that the heterocyclic ring “A” of formula c) is represented by the formulas i ₁ ) and i ₂ ) Is selected from the group consisting of:

In a preferred embodiment of the invention, the heterocyclic ring "A" is selected from the group consisting of

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula j):

j)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH ₂ -,> S0 ₂ , -OCH ₂ -and -CH ₂ 0-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula k):

k)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula k) as defined in the paragraph above wherein the dashed line is a double bond.

In another embodiment of the invention, heterocyclic ring “A” has formula l):

l)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of _10), and heteroaryl, and preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ 0-, preferably Y is oxygen, -OCH _2- Or -CH ₂ 0-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has formula l) in which the dashed line is a double bond, so that the heterocyclic ring “A” of formula c) is represented by formulas l ₁ ) and l ₂ ) Is selected from the group consisting of:

In another embodiment of the invention, the heterocyclic ring “A” has the formula m):

m)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ 0-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, the heterocyclic ring “A” has the formula n):

n)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ 0-, more preferably Y is oxygen.

In another embodiment of the invention, heterocyclic ring “A” has formula o):

o)

Wherein, X is imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and the selected (C ₁ -C pyrazolyl from the group consisting of ₁₀ ) heteroaryl, preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl. In this embodiment, Y is selected from the group consisting of bond, oxygen, sulfur, -CH ₂ -,> SO ₂ , -OCH ₂ -and -CH ₂ O-, preferably Y is oxygen, -OCH _2- Or -CH ₂ O-, more preferably Y is oxygen.

In another embodiment of the invention, each R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is hydrogen, (C ₁ -C ₄ ) alkyl, (C _1- C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl and each of the above (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cyclo Alkyl and (C ₁ -C ₁₀ ) heterocyclyl are halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, -CN, -OH on ring carbon atoms that can form additional bonds And 1 to 3 substituents independently selected from -NH ₂ .

The general or more general embodiments of each of the above embodiments are each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are selected from the group consisting of hydrogen, (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl and (C ₃ -C ₈ ) cycloalkyl Compound.

Preferred or more general embodiments are R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13, respectively.} Is a compound of this embodiment selected from hydrogen and (C ₁ -C ₄ ) alkyl such as methyl.

In another embodiment of the invention, each R ⁵ , R ⁶ , R ⁷ and R ⁸ is hydrogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkenyl, (C ₁ -C ₄ ) Alkynyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl, and Each (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl Is one to three independently selected from halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, -CN, -OH and -NH ₂ on a ring carbon atom capable of forming additional bonds It may be optionally substituted with a substituent.

In another embodiment of the invention, one or two of R ⁵ , R ⁶ , R ⁷ and R ⁸ are groups other than hydrogen.

In another embodiment of the invention, R ⁹ is hydrogen, (C ₁ -C ₄ ) alkyl. Independently from (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl.

In another embodiment of the invention, R ⁹ is independently selected from hydrogen and (C ₁ -C ₄ ) alkyl such as methyl.

In another embodiment of the present invention, Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl , 1,3-oxazolidin-4-one-5-yl, 1,3-oxazolidine-2,4-dione-5-yl, 4,5-dihydro-1,2-oxazolidine- 3-one-4-yl, 1,3-thiazolidin-4-one-5-yl, 1,3-thiazolidine-2,4-dione-5-yl, 1,3-imidazolidine -4-one-5-yl, 1,3-imidazolidin-2,4-dione-5-yl, 1,2-pyrazolidin-3-one-4-yl, tetrahydro-1,3 -Oxazin-4-one-5-yl, tetrahydro-1,3-oxazine-2,4-dione-5-yl, morpholinyl, morpholin-3-one-2-yl, morpholine- 3,5-dione-2-yl, 2,3-dihydro-1,4-oxazin-3-one-2-yl, tetrahydro-1,3-thiazin-4-one-5-yl, Tetrahydro-1,3-thiazine-2,4-dione-5-yl, thiomorpholinyl, thiomorpholin-3-one-2-yl, thiomorpholin-3,5-dione-2-yl , 2,3-dihydro-1,4-thiazin-3-one-2-yl, hexahi Rho-1,2-diazin-3-one-4-yl, 4,5-dihydro-2H-pyridazin-3-one-4-yl, hexahydro-1,3diazine-2,4- Dion-5-yl, piperazine-2-one-3-yl, piperazine-2,6-dione-3-yl, tetrahydro-1,3,4-thiadiazine-5-one-6-yl , 5,6-dihydro-1,3,4-thiadiazine-5-one-6-yl, 1,3,4-oxadiazine-5-one-6-yl, 5,6-dihydro -1,2,4-oxadiazine-5-one-6-yl, tetrahydro-1,2,4-oxadiazine-5-one-6-yl, 1,2,4-triazine-5 -One-6-yl, tetrahydro-1,2,4-oxadiazine-5-one-6-yl, 5,6-dihydro-1,2,4-oxadiazine-5-one-6 (C ₃ -C ₈ ) selected from the group consisting of -yl, 1,2,4-oxadiazine-3,5-dione-6-yl and 1,2,4-triazine-6-one-5-yl Cycloalkyl or (C ₁ -C ₁₀ ) heterocyclyl. In this embodiment, preferably Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-methylpiperidinyl and morpholinyl. In this embodiment, more preferably Z is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. In this embodiment, most preferably Z is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.

In another embodiment of the invention, Z is benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benz Oxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, isoindolinyl, isoquinolinyl, Isothiazolyl, isoxazolyl, naphthyridinyl, oxadizolyl, oxazolyl, phthalazinyl, putridinyl, furinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, Group consisting of quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, more preferably pyridinyl, pyrazinyl, pyridazinyl and pyrazolyl (C ₁ -C ₁₀ ) heteroaryl selected from, wherein (C ₁ -C ₁₀ ) heteroaryl is A valence bond on a ring carbon atom that can form F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C ₁ -C ₄₎ perfluoroalkyl, (C ₁ -C ₄₎ Purple Optionally substituted with one or two substituents independently selected from uroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy.

In another embodiment of the invention, one of X or Z is F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C _1- ) on a ring carbon atom capable of forming additional bonds. Substitution with one or two substituents independently selected from C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy do.

In another embodiment of the invention, both X and Z form F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) on ring carbon atoms capable of forming additional bonds. Perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -wherein p is 0, R ¹⁵ is selected from the group consisting of halo, -CN, and R ¹⁸ , R ¹⁸ is hydrogen, (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) Heterocyclyl selected from the group consisting of (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties on ring carbon atoms capable of forming an additive combination of F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C ₁ -C ₄₎ perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈₎ by a substituent independently selected from cycloalkyloxy it may be optionally substituted 1 to 3 times per ring, wherein the (C ₃ -C ₈₎ cycloalkyl and (C ₁ -C ₁₀₎ heterocyclyl residues are also By oxo, and optionally may be substituted, the (C ₁ -C ₁₀₎ heteroaryl and (C ₁ -C ₁₀₎ heterocyclyl residues are on a ring nitrogen atoms which may further have a substituent group (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ alkyl - (C = O) - by a moiety independently selected from the group consisting of may be optionally substituted one to two times per ring.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 0-4, preferably 1-2, and R ¹⁵ is halo, -CN, -N0 ₂ , OH, (C ₁ -C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₁ -C ₄ ) perfluoroalkyl, perfluoro (C ₁ -C ₄ ) alkoxy, ^{R 18 -, R 18 -O-,} R 18 - (C 1 -C 4) alkyl, ^{-O-, R 18 - (C =} O) -, R 18 - (C = O) -O-, R 18 - O- (C = O)-, R ¹⁸ -S-, R ^22- (S = O)-, R ^18- (SO ₂ )-, R ^22- (SO ₂ )-(NR ²¹ )-, R ¹⁹ -(C = O)-(NR ²¹ )-, R ²² -O- (C = O)-(NR ²¹ )-, (R ¹⁹ R ²⁰ ) N-, (R ¹⁹ R ²⁰ ) N- (SO ₂ )-, (R ¹⁹ R ²⁰ ) N- (C = O)-, (R ¹⁹ R ²⁰ ) N- (C = O)-(NR ²¹ )-and (R ¹⁹ R ²⁰ ) N- (C = O ) Is selected from the group consisting of -O, each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl, R ¹⁸ is hydrogen, (C ₁ -C ₄ ) alkyl, (C _6- C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl, wherein the (C ₆ -C ₁₀ ) aryl , (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) Heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ ) on ring carbon atoms that may form additional bonds ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C _1- C ₄ ) alkyl] may be optionally substituted 1 to 3 times per ring by a substituent independently selected from ₂ -N- and (C ₃ -C ₈ ) cycloalkyloxy, wherein (C ₃ -C ₈ ) cycloalkyl and The (C ₁ -C ₁₀ ) heterocyclyl moiety may also be optionally substituted by oxo, wherein the (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moiety have additional substituents. Optionally substituted 1-2 times per ring by a substituent independently selected from the group consisting of (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkyl- (C═O) — on a ring nitrogen atom have.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1, R ¹⁵ is (R ¹⁹ R ²⁰ ) N-, and each R ¹⁶ or R ¹⁷ is independently hydrogen and each R ¹⁹ and R ²⁰ is hydrogen or (C ₁ -C ₁₀ ) heteroaryl such as 2-oxazolyl, 2-pyrazolyl or 3-pyrazolyl.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 and R ¹⁵ is (R ¹⁹ R ²⁰ ) N- (C = O)-( NR ²¹ )-, each R ¹⁶ or R ¹⁷ is independently hydrogen, each R ¹⁹ and R ²⁰ is (C ₁ -C ₄ ) alkyl, together with the nitrogen to which they are attached form a 3 to 8 membered ring And R ²³ is selected from the group consisting of hydrogen and (C ₁ -C ₄ ) alkyl.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 and R ¹⁵ is R ²² -O- (C = 0)-(NR ²¹ ) -Each R ¹⁶ or R ¹⁷ is independently hydrogen, R ²¹ is selected from the group consisting of hydrogen and (C ₁ -C ₄ ) alkyl, R ²² is (C ₁ -C ₄ ) alkyl and (C ₃ -C ₈ ) cycloalkyl, such as methyl, ethyl, propyl, butyl or cyclobutyl.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1, R ¹⁵ is R ^19- (C = 0)-(NR ²¹ ), Each R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl and R ¹⁹ and R ²¹ together with the carbon or nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 and R ¹⁵ is (R ¹⁹ R ²⁰ ) N- (C = O)-( NR ²¹ ), each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ¹⁹ and R ²¹ together with the nitrogen to which they are attached form a 3-8 membered heterocyclic ring .

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 and R ¹⁵ is R ²² -O- (C = 0)-(NR ²¹ ) And each R ¹⁶ and R ¹⁷ are independently hydrogen or (C ₁ -C ₄ ) alkyl and R ²¹ and R ²² together with the nitrogen or oxygen to which they are attached form a 3-8 membered heterocyclic ring .

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -wherein p is 1 to 4, preferably 1 and R ¹⁵ is halo, -CN and R ¹⁸ Each R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl, wherein R ¹⁸ is hydrogen, (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) Aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl, wherein (C ₆ -C ₁₀ ) aryl, ( C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are F, Cl, Br, CN on ring carbon atoms which may form additional bonds , OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ 1 to 3 times per ring by a substituent independently selected from -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈ ) cycloalkyloxy May be optionally substituted with the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl moiety may also be optionally substituted with oxo, and the (C ₁ -C ₁₀ ) heteroaryl And the (C ₁ -C ₁₀ ) heterocyclyl moiety consists of (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkyl- (C═O) — on a ring nitrogen atom which may have additional substituents Optionally substituted 1-2 times per ring by substituents independently selected from the group.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -wherein p is 1 to 4, preferably 1 and R ¹⁵ is selected from the group consisting of R ¹⁸ And each R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl and R ¹⁸ is selected from the group consisting of hydrogen and (C ₁ -C ₄ ) alkyl.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 to 4, preferably 1 and R ¹⁵ is (R ¹⁹ R ²⁰ ) N -, (R ¹⁹ R ²⁰ ) N- (C = O), (R ¹⁹ R ²⁰ ) N- (SO ₂ ), (R ¹⁹ R ²⁰ ) N- (C = O)-(NR ²¹ )-and ( R ¹⁹ R ²⁰ ) N- (C═O) —O, wherein each R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ¹⁹ and R ²⁰ are they Together with the nitrogen to which it is attached form a 3-8 membered heterocyclic ring.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1-4, preferably 1, and R ¹⁵ is R ^19- (C = 0) )-(NR ²¹ )-, (R ¹⁹ R ²⁰ ) N- (C = O)-(NR ²¹ ), -NR ¹⁹ R ²⁰ , (R ¹⁹ R ²⁰ ) N- (C = O)-(NR ²¹ )-, R ²² (S = O)-, R ^22- (SO ₂ )-(NR ²¹ )-, R ²² -O- (C = O)-(NR ²¹ )-and (R ¹⁹ R ²⁰ ) N Each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl, and each of R ¹⁹ , R ²⁰ and R ²¹ is hydrogen; , Consisting of (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl Independently selected from the group wherein said (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are additional a combination of on the ring carbon atoms capable of forming F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C ₁ -C ₄₎ perfluoroalkyl, (C ₁ -C ₄₎ Purple Luoroalkoxy From (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈ ) cycloalkyloxy Optionally substituted with 1 to 3 substituents independently selected, and the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl moieties may also be optionally substituted by oxo, and ( C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkyl- on ring nitrogen atoms which may have additional substituents. Optionally substituted 1-2 times per ring by a substituent independently selected from the group consisting of (C═O) —, R ²² is (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, ( C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl, and (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀₎ heteroaryl and (of C ₁ -C ₁₀₎ heterocyclyl residues are added On the ring carbon atoms capable of forming the sum F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C ₁ -C ₄₎ perfluoroalkyl, (C ₁ -C ₄₎ perfluoroalkyl Roalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈ ) cycloalkyl Optionally substituted with 1 to 3 substituents independently selected from oxy, wherein the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterosyrylyl moieties may also be optionally substituted by oxo , Wherein the (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) on a ring nitrogen atom which may have additional substituents. Optionally substituted 1-2 times per ring by a substituent selected from the group consisting of alkyl- (C═O) —.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1-4, preferably 1, and R ¹⁵ is R ^19- (C = 0) )-(NR ²¹ )-, R ¹⁹ -O- (C = 0)-(NR ²¹ )-and (R ¹⁹ R ²⁰ ) N- (C = 0)-(NR ²¹ ), Each R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl and R ¹⁹ and R ²¹ together with the nitrogen, carbon or oxygen to which they are attached form a 3-8 membered heterocyclic ring.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , where p is 0 and G is oriented at a position other than the alpha position relative to the point of attachment of the Z ring and Y do.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -wherein p is 0 and G is oriented in the meta position relative to the point of attachment of the Z ring and Y.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1-4, preferably 1, and G is at the point of attachment of the Z ring and Y Is oriented at a position other than the alpha position.

In another embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1-4, preferably 1, and G is at the point of attachment of the Z ring and Y Is oriented at the meta position relative to.

In another preferred embodiment of the invention, ^one or ^{two of} R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are groups excluding hydrogen.

In a more preferred embodiment of the invention, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is Hydrogen.

In another preferred embodiment of the invention, either X or Z is not substituted with any arbitrary substituent.

In another preferred embodiment of the invention, neither X nor Z is substituted with any optional substituent.

In another preferred embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -wherein p is 0 and R ¹⁵ is halo, -CN and (C ₁ -C ₁₀ ) heteroaryl It is selected from the group consisting of. More preferably, R ¹⁵ is bromo, fluoro, -CN or oxadiazolyl, preferably [1,3,4] oxadiazol-2-yl.

In another preferred embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 0 or 1, R ¹⁵ is R ¹⁸ , and each of R ¹⁶ and R ¹⁷ is Hydrogen and R ¹⁸ is independently hydrogen or (C ₁ -C ₄ ) alkyl, preferably methyl.

In another preferred embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -wherein p is 0 or 1 and G is oriented in the meta position relative to the point of attachment of the Z ring and Y do.

In another preferred embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 and R ¹⁵ is R ^19- (C = 0)-(NR ²¹ )- Each R ¹⁶ or R ¹⁷ is independently hydrogen, R ¹⁹ is (C ₁ -C ₄ ) alkyl, more preferably methyl, ethyl, or butyl, or (C ₃ -C ₈ ) cycloalkyl, More preferably, it is cyclobutyl, and R <^21> is hydrogen.

In another preferred embodiment of the invention, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , wherein p is 1 and R ¹⁵ is (C ₁ -C ₁₀ ) heteroaryl, such as 2-pyra Is jolyl and each of R ¹⁶ and R ¹⁷ is independently hydrogen.

In another preferred embodiment of the invention, the heterocyclic ring “A” has the formula a) or b):

Wherein X is (C ₁ -C ₁₀ ) heteroaryl selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably X is pyridinyl, Y is a bond, oxygen, _{sulfur, -CH 2 -,> SO 2} , -OCH 2 - and -CH ₂ O-, more preferably Y is oxygen, -OCH ₂ - or -CH ₂ O-, and, most preferably, Y is oxygen to be.

Other preferred compounds of the invention are those wherein the heterocyclic ring “A” is (C ₁ -C ₁₀ ) heteroaryl wherein X is selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl, more preferably Is a compound I having Formula a) or b) as defined above wherein X is pyridinyl and most preferably pyridinyl has the following formula a ") or b") with an "A" ring and a YZG group: Compounds of include:

Wherein Y is a bond, oxygen, sulfur, -CH ₂ -,> S0 ₂ , -OCH ₂ -or -CH ₂ O-, preferably Y is oxygen, -OCH ₂ -or -CH ₂ O- , More preferably, Y is oxygen.

Other preferred compounds of the invention include those wherein the heterocyclic ring “A” is X is pyridinyl, most preferably the pyridinyl is defined with the “A” ring and the YZG group as defined above in formula a ”) or b”). Wherein Y is oxygen, Z is (C ₆ -C ₁₀ ) aryl, preferably phenyl, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p −, where p is 1 and R ¹⁵ Is (C ₁ -C ₁₀ ) heteroaryl, such as 2-pyrazolyl, and each of R ¹⁶ and R ¹⁷ is independently hydrogen or (C ₁ -C ₄ ) alkyl, such as methyl, preferably hydrogen, and G is Included are compounds of formula I having formula a) or b) as defined above, oriented in the para position with respect to the point of attachment of the Z ring and Y.

Most preferred compounds of the invention include those wherein the heterocyclic ring “A” is X is pyridinyl, most preferably the pyridinyl is defined with the “A” ring and the YZG group as defined above in formula a ”) or b”). Wherein Y is oxygen, Z is (C ₆ -C ₁₀ ) aryl, preferably phenyl, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p −, where p is 0 and R ¹⁵ Is a hydrogen, -CN, halo and oxadiazolyl, wherein I has formula a) or b) as defined above, oriented in a para position relative to the point of attachment of the Z ring and Y Compounds of

Other most preferred compounds of the present invention are those wherein the heterocyclic ring “A” is X is pyridinyl, most preferably the pyridinyl is defined with the “A” ring and the YZG group as defined above in formula a ”) or b” ), Y is oxygen, Z is (C ₆ -C ₁₀ ) aryl, preferably phenyl, G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , where p is 1 and R ¹⁵ is R ^19- (C═O) — (NR ²¹ ) —, each of R ¹⁶ and R ¹⁷ is independently hydrogen, and R ¹⁹ is (C ₁ -C ₄ ) alkyl and (C ₃ -C ₈ ) Cycloalkyl, such as methyl, ethyl, propyl, butyl or cyclobutyl, R ²¹ is selected from the group consisting of hydrogen or (C ₁ -C ₄ ) alkyl, G is the point of attachment of the Z ring and Y Included are compounds of formula (I) having formula (a) or b) as defined above, oriented in the para position for.

Other compounds of the present invention

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane- 2,7,9,11-tetraone;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane -2,6,8,10-tetraone;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,3,8,10-tetraaza-spiro [5.5] Cann-2,7,9,11-tetraone;

4- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,1-dioxo-1λ ⁶ -thia-2,4, 7,9-tetraaza-spiro [4.5] decane-3,6,8,10-tetraone;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane -2,4,6,8,10-pentanone;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2λ ⁶ -thia-1,7, 9-triazaspiro [4.5] decane-6,8,10-trione;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2λ ⁶ -thia-1,8, 10-triazaspiro [5.5] undecane-7,9,11-trione;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-6 , 8,10-trione;

1- [6- (4-cyclobutylmethoxymethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone ;

1- {6- [4- (2-oxo-pyrrolidin-1-ylmethyl) -phenoxy] -pyridin-3-yl} -1,7,9-triazaspiro [4.5] decane-2, 6,8,10-tetraone;

1- [6- (1H-indazol-5-yloxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -3-methyl-1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetra On;

1- [6- (3-Fluoro-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone;

4- [5- (2,7,9,11-tetraoxo-1,8,10-triaza-spiro [5.5] undes-1-yl) -pyridin-2-yloxy] -benzonitrile;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

N- {4- [5- (2,7,9,11-Tetraoxo-1,8,10-triaza-spiro [5.5] undes-1-yl) -pyridin-2-yloxy] -benzyl } -Acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,7,9,11-tetraoxo-1,8,10-triaza-spiro [5.5] undes-1-yl) -pyridine-2- Iloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11 -Tetraone;

1- [6- (4-fluoro-phenoxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,6,8,10-tetraone;

4- [5- (2,6,8,10-tetraoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (2,6,8,10-Tetraoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy]- Benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridine-2 -Yloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,6,8, 10-tetraone;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,3,8,10-tetraaza-spiro [5.5] undecane-2,7,9,11-tetraon ;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,3,8,10-tetraaza-spiro [5.5] undecane-2,7,9,11-tetraone;

4- [5- (2,7,9,11-tetraoxo-1,3,8,10-tetraaza-spiro [5.5] undes-1-yl) -pyridin-2-yloxy] benzonitrile;

N- {4- [5- (2,7,9,11-tetraoxo-1,3,8,10-tetraaza-spiro [5.5] undes-1-yl) -pyridin-2-yloxy] Benzyl] -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,7,9,11-tetraoxo-1,3,8,10-tetraaza-spiro [5.5] undes-1-yl) -pyridine- 2-yloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,8,10-tetraaza-spiro [5.5] undecane-2,7,9 , 11-tetraone;

4- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,1-dioxo-1λ ⁶ -thia-2,4,7,9- tetraaza-spiro [4.5] decane -3,6,8,10-tetraone;

4- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,1-dioxo-1λ ⁶ -thia-2,4,7,9-tetraaza-spiro [4.5] decane- 3,6,8,10-tetraone;

4- [5- (1,1,3,6,8,10-hexaoxo-1λ ⁶ -thia-2,4,7,9-tetraaza-spiro [4.5] dec-4-yl) -pyridine- 2-yloxy] -benzonitrile;

N- {4- [5- (1,1,3,6,8,10-hexaoxo-1λ ⁶ -thia-2,4,7,9-tetraaza-spiro [4.5] dec-4-yl) -Pyridin-2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (1,1,3,6,8,10-hexaoxo-1λ ⁶ -thia-2,4,7,9-tetraaza-spiro [4.5] des -4-yl) -pyridin-2-yloxy] -benzylamide;

1,1-dioxo-4- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1λ ⁶ -thia-2,4, 7,9-tetraaza- Spiro [4.5] decane-3,6,8,10-tetraone;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,4,6,8,10-penta On;

4- [5- (2,4,6,8,10-pentaoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzo Nitrile;

N- {4- [5- (2,4,6,8,10-pentaoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy ] -Benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,4,6,8,10-pentaoxo-1,3,7,9-tetraaza-spiro [4.5] dec-1-yl) -pyridine -2-yloxy] -benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,4,6, 8,10-pentanone;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,3,7,9-tetraaza-spiro [4.5] decane-2,4,6,8,10-pentaone ;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -2,2-dioxo-2λ ⁶ -thia-1,7,9-triaza-spiro [4.5] decane-6 , 8,10-trione;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2λ ⁶ -thia-1,7,9-triaza-spiro [4.5] decane-6, 8,10-trione;

4- [5- (2,2,6,8,10-pentaoxo-2λ ⁶ -thia-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy ] -Benzonitrile;

N- {4- [5- (2,2,6,8,10-Pentanoxo-2λ ⁶ -thia-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridine-2 -Yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,2,6,8,10-pentaoxo-2λ ⁶ -thia-1,7,9-triazaspiro [4.5] dec-1-yl) -Pyridin-2-yloxy] -benzylamide;

2,2-dioxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -2λ ⁶ -thia-1,7,9-triazaspiro [4.5 ] Decane-6,8,10-trione;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -2,2-dioxo-2λ ⁶ -thia-1,8,10-triazaspiro [5.5] undecane-7 , 9,11-trione;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -2,2-dioxo-2λ ⁶ -thia-1,8,10-triazaspiro [5.5] undecane-7, 9,11-trione;

4- [5- (2,2,7,9,11-pentaoxo-2λ ⁶ -thia-1,8,10-triaza-spiro [5.5] undes-1-yl) -pyridin-2-yljade Cy] -benzonitrile;

N- {4- [5- (2,2,7,9,11-pentaoxo-2λ ⁶ -thia-1,8,10-triaza-spiro [5.5] undes-1-yl) -pyridine- 2-yloxy] -benzyl} -acetamide;

Azetidine-1-carboxylic acid 4- [5- (2,2,7,9,11-pentaoxo-2λ ⁶ -thia-1,8,10-triazaspiro [5.5] undes-1-yl ) -Pyridin-2-yloxy] -benzylamide;

2,2-dioxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -2λ ⁶ -thia-1,8,10-triazaspiro [5.5 ] Undecane-7,9,11-trione;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-6,8,10-trione;

1- [6- (4-Fluoro-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-6,8,10-trione;

4- [5- (6,8,10-trioxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzonitrile;

N- {4- [5- (6,8,10-Trioxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} -acet amides;

Azetidine-1-carboxylic acid 4- [5- (6,8,10-trioxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] Benzylamide;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-6,8,10-trione ;

1- [6- (3-Fluoro-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5 ] Undec-2,7,9,11-tetraone;

1- [6- (2-Fluoro-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5 ] Undec-2,7,9,11-tetraone;

1- [6- (3-Methyl-4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,8,10-triazaspiro [5.5] Undecane-2,7,9,11-tetraon;

1- [4- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -phenyl] -1,8,10-triaza-spiro [5.5] undecane-2,7, 9,11-tetraone;

1- [6- (pyridin-4-yloxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

1- [5- (pyridin-4-yloxy) -pyridin-2-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

1- [4- (pyridin-4-yloxy) -phenyl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

1- [4- (pyridin-4-yloxy) -phenyl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone;

Azetidine-1-carboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yljade ] -Benzylamide

And pharmaceutically acceptable salts thereof.

Preferred specific compounds of formula (I)

1- [6- (4-fluoro-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-fluoro-phenoxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone;

4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzonitrile;

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2 , 6,8,10-tetraone;

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone;

N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} Acetamide;

N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} Propionamide;

N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} Butyramide;

Pentanic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide;

Cyclobutanecarboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy]- Benzylamide;

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone;

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10- Tetraon

And pharmaceutically acceptable salts thereof.

The invention also relates to connective tissue diseases, inflammatory diseases, immune / allergic diseases, infectious diseases in mammals, including humans, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, Characterized by metalloproteinase activity and symptoms selected from the group consisting of respiratory disease, cardiovascular disease, eye disease, metabolic disease, central nervous system (CNS) disease, liver / kidney disease, genital health disease, gastric disease, skin disease and cancer It relates to a pharmaceutical composition for the treatment of other diseases.

The invention also provides a pharmaceutical for the inhibition of matrix metalloproteinases or other metalloproteinases involved in matrix degradation in mammals, including humans, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof To a composition.

The invention also includes administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal, including human, connective tissue disease, inflammatory disease, immune / allergic disease, infectious disease in said mammal. Matrix metalloproteinase activity and symptoms selected from the group consisting of respiratory disease, cardiovascular disease, eye disease, metabolic disease, central nervous system (CNS) disease, liver / kidney disease, genital health disease, gastric disease, skin disease and cancer The present invention relates to a method for treating another disease.

The present invention also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal, including a human, in a matrix metalloproteinase or other metalloproteins associated with matrix degradation in said mammal. It relates to a method for suppressing naase.

We have found that inhibitors of formula I with different metalloprotease activity (preferably MMP-13 inhibitory activity) can be identified. One group of preferred inhibitors of formula (I) that can be identified by the present inventors includes the selective selective inhibition of MMP-13 over MMP-1. Compounds of the invention also have selectivity over a group of related enzymes known as leprolysine, such as TACE and agrecanase. Another preferred group of inhibitors of formula (I) that can be identified by the present inventors include the selective selective inhibition of MMP-13 over MMP-1 and MMP-14. Another preferred group of inhibitors of formula (I) that can be identified by the inventors include the preferentially inhibiting MMP-13 over MMP-1 and 12. Another preferred group of inhibitors of formula (I) that can be identified by the present inventors include the selective selective inhibition of MMP-13 over MMP-1, 2 and 14. Another preferred group of inhibitors of Formula (I) that can be identified by the inventors include the preferentially selective inhibition of MMP-13 over MMP-1, 2, 3, 7, 9 and 14. Most preferred compounds of the present invention preferentially selectively inhibit MMP-13 over MMP-1, 2, 3, 7, 9, 12 and 14 and mammalian leprolysine.

The term "treating" as used herein refers to reversing, alleviating, inhibiting or preventing the progression of the disease or condition to which the term applies, or one or more symptoms of the disease or condition. The term "treatment" as used herein refers to the act of "treating" as defined above.

As used herein, “connective tissue disease” refers to diseases such as degenerative cartilage loss after traumatic joint injury, osteoarthritis, osteoporosis, Paget's disease, relaxation of artificial joint grafts, periodontal disease and gingivitis.

As used herein, "destruction of articular cartilage" refers to a combination that causes articular cartilage destruction, preferably joint damage, reactive arthritis, acute pyrophosphate arthritis (caustic gout), psoriatic arthritis, or combustible rheumatoid arthritis, more preferably osteoarthritis. Indicates tissue disease.

As used herein, “inflammatory disease” refers to diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, cartilage calcification, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease and cachexia.

As used herein, “immune / allergic disease” includes diseases associated with organ transplant toxicity, allergic reactions, allergic contact hypersensitivity, autoimmune diseases such as granulomatous inflammation / tissue remodeling (eg, asthma), immunosuppression and sarcoma Diseases such as

As used herein, “infectious diseases”, including diseases mediated by viral, bacterial, fungal or microbial infections, include septic arthritis, AIDS, fever, Prion disease, myasthenia gravis, malaria, sepsis, hemodynamic shock and plaque Diseases such as blood shock.

As used herein, "respiratory disease" includes diseases such as chronic obstructive pulmonary disease (including emphysema), acute respiratory distress syndrome, asthma, peroxidative alveolar damage and idiopathic pulmonary fibrosis and other fibrotic lung diseases.

As used herein, “cardiovascular disease” includes atherosclerosis, including atherosclerotic plaque rupture; Aortic aneurysms, including abdominal aortic aneurysms and cerebral aortic aneurysms; Congestive heart failure; Myocardial infarction and cerebral infarction; apoplexy; Cerebral ischemia; Coagulation and acute phase reactions; Left ventricular dilatation; Reperfusion injury after ischemia; Vasculitis fibrosis; Angiopathy; And diseases such as restenosis.

As used herein, “eye disease” includes aberrant angiogenesis, ocular angiogenesis, eye inflammation, keratoconus, Sjogren syndrome, myopia, ocular tumor, corneal graft rejection, corneal injury, neovascular glaucoma, corneal ulcer, corneal scar , Macular degeneration (including "age related macular degeneration (ARMD)" including wet and dry), proliferative vitreoretinopathy and prematurity retinopathy.

As used herein, “metabolic disease” refers to a disease such as diabetes (including insulin-independent diabetes mellitus, diabetic retinopathy, insulin resistance, diabetic ulcers).

As used herein, "central nervous system" (CNS) diseases include head trauma, spinal cord injury, inflammatory diseases of the central nervous system, neurodegenerative diseases (acute and chronic), Alzheimer's disease, demyelinating diseases of the nervous system, Huntington ), Diseases such as Parkinson's disease, peripheral neuropathy, pain, cerebral amyloid angiopathy, cognitive or cognitive improvement, amyotrophic lateral sclerosis, multiple sclerosis, migraine, depression and anorexia.

As used herein, “liver / kidney disease” refers to diseases such as nephrotic syndrome, such as glomerulonephritis and glomerular disease of the kidneys, proteinuria, cirrhosis and interstitial nephritis.

As used herein, “genital health disease” refers to diseases such as endometriosis, contraception (male / female), dysmenorrhea, dysfunctional uterine bleeding, premature rupture of the fetal membrane and abortion.

As used herein, “stomach disease” refers to diseases such as colonic splice and gastric ulcer.

As used herein, “skin disease” includes skin aging, pressure sores, psoriasis, eczema, dermatitis, radiation damage, tissue ulcers, pressure ulcers, bullous epidermal detachment, abnormal wound healing (topical and oral preparations), burns and scleritis Indicates a disease.

As used herein, “cancer” includes solid tumor cancers such as colon cancer, breast cancer, lung cancer and prostate cancer, tumor infiltration, tumor growth, tumor metastasis, oral and pharyngeal cancers (lip cancer, tongue cancer, pharyngeal cancer, pharyngeal cancer), esophageal cancer, Gastric cancer, small intestine cancer, colon cancer, rectal cancer, liver cancer, bile cancer, pancreatic cancer, laryngeal cancer, lung cancer, bone cancer, connective tissue cancer, skin cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer and other bladder tissues Lymphomas, including hematologic and lymphoid, granulocytic and monocytic, including cancer, eye cancer, brain cancer, central nervous system cancer, thyroid cancer and other endocrine adenocarcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and leukemia Shows the same disease.

The present invention also encompasses isotopically-labeled compounds that are identical to the compounds of formula (I) but whose one or more elements are replaced with atoms having an atomic weight or atomic number that is different from the atomic weight or atomic number usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively. , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of such compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are included within the scope of the present invention. Certain isotopically-labelled compounds of the invention, such as those into which radioisotopes such as ³ H and ¹⁴ C have been introduced, are useful in drug and / or substrate tissue distribution analysis. Tritium, ie ³ H and carbon-14, ie ¹⁴ C isotopes are particularly preferred due to their ease of preparation and detection. Also, deuterium, i.e., in a more specific therapeutic benefit when substituted with a heavy isotope due to the more improved the metabolic stability, for the example, increased in vivo half-life or reduced dosage requirements, such as ² H may be obtained, in which case May be preferred. Isotope-labeled compounds of formula (I) and prodrugs thereof of the present invention are generally isotopes that are readily available for isotopically-labeled reagents by carrying out the procedures set forth in the following schemes and / or examples and preparations. It can be prepared by substituting with a labeled reagent.

The present invention also includes pharmaceutical compositions containing prodrugs of the compounds of formula (I). The invention also includes a method of treating or preventing a disease that can be treated or prevented by inhibition of a matrix metalloproteinase or inhibition of mammalian leprolysine, comprising administering a prodrug of a compound of Formula (I). . Compounds of formula (I) having free amino, amido, hydroxy, sulfonamide or carboxyl groups can be converted to prodrugs. Prodrugs include amino acid residues or polypeptide chains of two or more (eg 2, 3 or 4) amino acid residues via peptide bonds to the free amido, amino, hydroxy or carboxylic acid groups of the compounds of formula (I). Covalently bound compounds are included. Amino acid residues include 20 natural amino acids, usually in three letters, 4-hydroxyproline, hydroxylysine, democin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-amino Butyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone are also included. Prodrugs also include compounds in which carbonates, carbamates, amides and alkyl esters are covalently bonded to the substituents of formula (I) via the carbonyl carbon of the prodrug side chain. Prodrugs also include dimers of compounds of formula (I).

Those skilled in the art will appreciate that the compounds of the present invention are useful for the treatment of various diseases. Those skilled in the art will also appreciate that when using a compound of the invention in the treatment of a particular disease, the compound of the invention may be used in combination with a variety of existing therapeutic agents for use in the disease.

For the treatment of rheumatoid arthritis, the compounds of the invention may be treated with TNF-α inhibitors such as anti-TNF monoclonal antibodies (such as infliximab, D2E7 and CDP-870) and TNF receptor immunoglobulin molecules (such as etanercept) , ICE inhibitors, MEKK1 inhibitors, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib and etoricoxib; Low-dose methotrexate, repunimide, steroid, glucosamine, chodrosamine / sulfate, gabapentin, A-agonists, IL-1 processing and release inhibitors, IL-1 receptor antagonists such as Kineret®, It can be combined with agents such as CCR-1 antagonists, hydroxychloroquine, d-penicylamine, auranopine or parenteral or oral gold.

The compounds of the present invention can be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Agents suitable for use in combination include standard nonsteroidal anti-inflammatory drugs (hereinafter NSAIDs) such as pyroxicam, diclofenac, propionic acid such as naproxen, flubiprofen, phenopropene, ketoprofen and ibuprofen, phena Mates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolone such as phenylbutazone, salicylate such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, paracoxib, et Toricoxib and rofecoxib, analgesics, steroids, glucosamine, chodrosamine / sulfate, gabapentin, A-agonists, IL-1 processing and release inhibitors, CCR-1 antagonists, LTD-4, LTB-4 and 5- LO inhibitors, p38 kinase inhibitors and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalan and mysticsk.

The compounds of the present invention may also be used in conjunction with anticancer agents such as endostatin and angiostatin or cytotoxic agents such as adriamycin, daunomycin, cis-platinum, etoposide, paclitaxel, docetaxel and alkaloids such as vincristine and antimetabolic agents such as methotrexate. It can be used in combination.

The compounds of the present invention may also contain cardiovascular agents such as calcium channel blockers (such as amlodipine and nifedipine), lipid lowering agents such as statins (such as lovastatin, atorvastatin, pravastatin and simvastatin), adrenergic agents such as doxazosin and terrazosin; Fibrates, beta-blockers, Ace inhibitors (eg, captopril, ricinopril, fosinopril, enalapril and quinapril), angiotensin-2 receptor antagonists such as losartan and irbesartan; It can be used in combination with nitrates, CCBs, diuretics such as digitalis, and platelet aggregation inhibitors. The compounds of the present invention can also be used in combination with plaque rupture inhibitors such as statins, zitromax, NSAIDs (including aspirin), heparin, uraparin, absiksimab, TPA and platelet inhibitors. The compounds of the present invention can also be used in combination with therapeutic agents for stroke, such as NIF, NHEI and CCRIR antagonists.

Compounds of the present invention may also be used in CNS agents such as antidepressants (such as sertraline), antiparkinsonians (such as deprenyl, carbadopa, L-dopa, dopamine receptor agonists such as rofinirol, pergolide and Pramipexole; MAOB inhibitors such as selegin and lasagulin, catechol-O-methyl transferase inhibitors such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, NK-1 inhibitors, dopamine Agonists and neuronal nitric oxide synthase inhibitors), and antialzheimer's agents such as donepezil, tacrine, COX-2 inhibitors, propopentophylline or metriponate.

The compounds of the present invention can also be used in combination with osteoporosis agents such as roloxifene, droroxifene, lasopoxifen or posomax and immunosuppressants such as FK-506 and rapamycin.

The compounds of the present invention are also useful for treating respiratory diseases, such as PDE-IV inhibitors, steroids such as fluticasone, triamcinolone, budesonide and beclomethasone, anticholinergic agents such as ifpratropium, sympathetic drugs such as salmeterol, Albuterol and xenophenex, decongestants such as fexofenadine, loratadine and cetirizine; Leukotriene antagonists such as zafirlukast and motelucast; And mast cell stabilizing agents such as giluton.

Compounds of the invention are also combined with therapeutic agents for skin diseases such as tretinoin, isotretinoin, steroids such as cortisone and mometasone, antibiotics such as tetracycline, antibacterial agents such as clotrimazole, myconazole and fluconazole and PDE-IV inhibitors Can be used.

The compounds of the present invention may also be used in the treatment of diabetes, such as insulin (including human or humanized insulin and inhaled insulin), aldose reductase inhibitors, sorbitol dehydrogenase inhibitors, antidiabetic agents such as biguanides such as metformin; Glitazones, glycosidase inhibitors such as acarbose, sulfonylureas such as glymepiride and glyphidide; And thiazolidinediones such as pioglitazone, rosiglitazone and troglitazone. Preferred combinations are useful for the treatment of diabetes side effects such as retinopathy, nephropathy and neuropathy, preferably retinopathy.

The following scheme illustrates the preparation of the compounds of the present invention. Unless stated otherwise, in the schemes and the description below, each of X, Y, Z, G, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ and R ²² are as defined above.

Scheme 1 shows a process for the preparation of compounds of formula (I). Referring to Scheme 1, compounds of formula I, wherein the heterocyclic ring “A” has formulas a to n (ie, each of the compounds of formulas Ia to In below) are those of formulas IIIa to 3 in the presence of a suitable base in a polar solvent Compounds of IIIn can be prepared by reacting with urea of formula II (ie, H ₂ N- (CO) -NH ₂ ), respectively:

Wherein L ¹ and L ² are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy.

Suitable bases include alkoxide bases such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, preferably sodium ethoxide. Suitable solvents include tetrahydrofuran, dimethylformamide or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide. The reaction described above is carried out for about 5 minutes to about 8 hours at a temperature of about 20 ° C to about 90 ° C, preferably about 50 ° C to about 80 ° C.

Compounds of formulas IIIa to IIIl can be prepared by reacting compounds of formulas IVa to IVl, respectively, with a suitable base in a polar solvent, respectively:

Wherein L ¹ and L ² are leaving groups such as alkoxy, preferably methoxy, ethoxy or benzyloxy, more preferably methoxy or ethoxy,

L ³ is a suitable leaving group such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs), preferably halo such as bromo or iodo.

Suitable bases include tertiary amines such as triethylamine. Other suitable bases include strongly basic macro-reticular resins or gel type resins such as Amberlyst 400® resin (hydroxide form). Suitable solvents include alcoholic solvents, preferably ethanol. The above reaction can be carried out for about 6 to about 36 hours at a temperature of about -10 ℃ to about 50 ℃, preferably about 20 ℃.

Compounds of formulas IIIm to IIIn can be prepared by reacting compounds of formulas IVm to IVn with a suitable base in a polar solvent, respectively, according to methods analogous to the preparation of compounds of formulas IIIa to IIIi, respectively:

Wherein L ³ is a suitable leaving group.

Suitable leaving groups of formula L ³ include halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs). Preferably L ³ is halo, such as chloro. The above-mentioned reaction may be carried out for about 1 hour to about 4 hours at a temperature of about 0 ° C to about 50 ° C, preferably about 20 ° C. Suitable solvents include tetrahydrofuran, dimethylformamide and alcohols.

Compounds of formulas (IVa) to (IVi) may each be prepared by reacting a compound of formula (VI) with a compound of formula (V):

L ^3- (A ')-L ⁴

(Ie, compounds of the formulas Va to Vi, respectively):

Wherein L ³ and L ⁴ are each suitable leaving groups such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs).

Preferably L ³ is halo, such as bromo, chloro or iodo. Preferably L ⁴ is chloro or fluoro. Optionally, the reaction described above may be carried out in the presence of a tertiary amine base such as N, N-dimethylaniline or pyridine, in the presence of a suitable solvent such as a hydrocarbon solvent (benzene or toluene), tetrahydrofuran or methylene chloride. The above reaction is carried out for about 30 minutes to about 6 hours at a temperature of about 20 ° C to about 90 ° C, preferably about 50 ° C to about 80 ° C.

Preferably, the reaction described above is carried out in an aromatic hydrocarbon solvent such as benzene or toluene in the absence of the base described above.

Compounds of formulas IVj to IVl can be prepared by reacting a compound of formula VI with formula V according to methods analogous to those described for the preparation of compounds of formulas IVa to IVi, respectively.

<Formula V>

L ^3- (A ')-L ⁴

(Ie, compounds of formula Vj to Vl, respectively):

Wherein L ³ and L ⁴ are each suitable leaving groups such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs).

Preferably L ³ is chloro, bromo or iodo. Preferably L ⁴ is chloro, bromo or iodo. The above reaction can be carried out for about 30 minutes to about 12 hours at a temperature of about 0 ° C to about 50 ° C, preferably about 20 ° C.

Compounds of formula (IVm) to (IVn) may be prepared by reacting a compound of formula (VI) with a compound of formula (V) following a method analogous to that described for the preparation of compounds of formulas IVa to IVi, respectively.

<Formula V>

L ^3- (A ')-L ⁴

(Ie, compounds of formula Vm to Vn, respectively):

Wherein L ³ and L ⁴ are each suitable leaving groups such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs).

Preferably L ³ is halo, such as chloro. Preferably L ⁴ is halo, such as chloro. The reaction described above may be carried out for about 30 minutes to about 8 hours at a temperature of about 0 ° C to about 80 ° C, preferably about 0 ° C to about 40 ° C.

Alternatively, compounds of formulas IVd, IVe and IVf may be prepared by reacting a compound of formula VI with a compound of formula V ', respectively.

(A ')-L ³

(Ie, compounds of the formulas Vd ', Ve' and Vf ', respectively):

Wherein L ³ is preferably halo, most preferably chloro, bromo or iodo. Optionally, the reaction described above may be carried out in the presence of a tertiary amine base in a suitable solvent. Suitable bases include N, N-dimethylaniline or pyridine. Suitable solvents include hydrocarbon solvents (benzene or toluene), tetrahydrofuran or methylene chloride, preferably aromatic hydrocarbon solvents such as benzene or toluene. The above reaction is carried out for about 30 minutes to about 6 hours at a temperature of about 20 ° C to about 90 ° C, preferably about 50 ° C to about 80 ° C. Preferably, the reaction described above is carried out in the absence of any aforementioned base.

Alternatively, compounds of formulas IVm and IVn can be prepared by reacting a compound of formula VI with a compound of formula V ', respectively.

<Formula V '>

(A ')-L ³

(Ie, compounds of the formulas Vm 'and Vn', respectively):

In the formula, L ³ is preferably halo, most preferably chloro.

The reaction described above may optionally be carried out in the presence of a tertiary amine base in a suitable solvent. Suitable bases include N, N-dimethylaniline or pyridine. Suitable solvents include hydrocarbon solvents (benzene or toluene), tetrahydrofuran or methylene chloride, preferably aromatic hydrocarbon solvents such as benzene or toluene. The above-mentioned reaction may be carried out for about 30 minutes to about 12 hours at a temperature of about -10 ° C to about 50 ° C, preferably about 0 ° C to about 30 ° C. Preferably, the reaction described above is carried out in the absence of any aforementioned base.

Compounds of formula VI can be prepared by reacting a compound of formula H ₂ NXYZG with a compound of formula VII:

Wherein L ¹ and L ² are leaving groups such as methoxy, ethoxy or benzyloxy; Preferably ethoxy;

L ⁵ is a leaving group such as halo, para-tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs); Preferably halo; Most preferably chloro or bromo.

The reactions described above can be carried out in the presence of a suitable base without solvent or in the presence of a suitable solvent, preferably without solvent. Suitable solvents include tetrahydrofuran or dimethylformamide. Suitable bases include weak tertiary amine bases, preferably tertiary aniline bases, most preferably N, N-dimethylaniline. Preferably, the reaction described above is carried out at a temperature of about 23 ° C. to about 100 ° C., preferably about 50 ° C. to about 90 ° C. for about 30 minutes to about 24 hours.

In the above reactions, the compounds of the respective formulas IVj to IVl can be isolated, but are preferably carried out in the next step without isolation. Thus, in Scheme 1, compounds of formula IIIj to IIIl are preferably prepared from a compound of formula VI by a single pot preparation method.

In the absence of isolating compounds of formulas IVj to IVl, suitable solvents for the single pot preparation process include dimethylformamide, tetrahydrofuran or alcohols, preferably alcohols such as ethanol. Preferably, single pot preparation is carried out in the presence of an alkoxide base, preferably sodium methoxide or sodium ethoxide. The single pot preparation described above is carried out at a temperature of about 40 ° C. to about 90 ° C., preferably about 60 ° C. to about 80 ° C. for about 15 minutes to about 12 hours.

Compounds of formula H ₂ NXYZG are either commercially available or can be prepared by methods well known to those skilled in the art. Alternatively, compounds of formula H ₂ NXYZG can be prepared as described in Scheme 3.

Compounds of formula (VII) are described in methods well known in the art, such as in PCT patent publication WO 98/58925 or described in The Organic Chemistry of Drug Synthesis, D. Lednicer and LA Mitscher, Volume 1, pages 167 to 277 and their It may be prepared by the method as outlined in the cited document. Each of the above published publications and applications are incorporated herein by reference in their entirety.

Compounds of formula (II) are commercially available or may be prepared by methods well known to those skilled in the art.

Scheme 2 shows a process for the preparation of a compound of formula I, ie, a compound of formula Io, wherein the heterocyclic ring “A” has formula o. Referring to scheme 2, compounds of formula Io are the compounds of formula IIIo in the presence of a suitable base in a polar solvent (here, L ¹ and L ² is a leaving group) with a urea of formula II (i.e., H ₂ N- (CO It can be prepared by reacting with) -NH ₂ ).

Suitable leaving groups include methoxy, ethoxy or benzyloxy, preferably ethoxy. Suitable bases include alkoxide bases such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, preferably sodium ethoxide. Suitable solvents include tetrahydrofuran, dimethylformamide or alcohols (such as ethanol), preferably tetrahydrofuran or dimethylformamide. The above-mentioned reaction is carried out for about 5 minutes to about 8 hours at a temperature of about 20 ℃ to about 90 ℃, preferably about 50 ℃ to about 80 ℃.

Compounds of formula (IIIo) can be prepared by reacting compounds of formula (IVo), where L ³ is a leaving group with a suitable base in a polar solvent. Suitable leaving groups include alkoxy (eg methoxy, ethoxy or benzyloxy) or halo; Preferably methoxy or ethoxy are included. Suitable bases include alkoxide bases, preferably sodium methoxide or sodium ethoxide. Suitable solvents include alcohols, preferably ethanol. The above-mentioned reaction may be carried out for about 1 hour to about 36 hours at a temperature of about 0 ° C to about 90 ° C, preferably about 60 ° C to about 90 ° C.

Compounds of formula IVo may be prepared by reacting a compound of formula VI with a compound of formula Vo in a suitable solvent:

Wherein L ⁶ is a suitable leaving group.

Suitable L ⁶ include alkoxy or halo such as chloro; Preferably alkoxy; More preferably methoxy or ethoxy. Optionally, the reaction described above may be carried out in the presence of a suitable tertiary amine base such as triethylamine, N, N-dimethylaniline or pyridine. Suitable solvents include hydrocarbon solvents (benzene or toluene), tetrahydrofuran or methylene chloride, preferably tetrahydrofuran. Preferably, the reaction described above is carried out in tetrahydrofuran or dimethylformamide in the presence of a suitable tertiary amine base described above. The above-mentioned reaction may be carried out for about 30 minutes to about 6 hours at a temperature of about 20 ℃ to about 90 ℃, preferably about 50 ℃ to about 80 ℃.

In the above reaction, the compound of formula IVo can be isolated but is preferably carried out to the next step without isolation. Thus, in Scheme 1, the compound of formula IIIo is preferably prepared from a compound of formula Vl by a single pot preparation method.

In the absence of isolating a compound of formula IVo, suitable solvents for the single pot preparation process include dimethylformamide, tetrahydrofuran or alcohols, preferably alcohols such as ethanol. The single pot preparation described above is suitably performed at a temperature of about 0 ° C. to about 70 ° C., preferably about 23 ° C. to about 60 ° C. for about 30 minutes to about 24 hours.

Compounds of formula VI can be prepared by reacting a compound of formula H ₂ NXYZG with a compound of formula VII as described in Scheme 1.

Scheme 3 shows a process for the preparation of compounds of formula H ₂ NXYZG which are useful intermediates for the preparation of compounds of formula I in Schemes 1 and 2. Referring to Scheme 3, a compound of Formula H ₂ NXYZG can be prepared by reacting a compound of Formula VII with a reducing agent, such as tin chloride II, in the presence of a suitable acid, such as hydrochloric acid, in a polar protic solvent. Suitable solvents include alcoholic solvents, water or mixtures thereof, preferably mixtures of ethanol and water. The above-mentioned reaction may be carried out for about 1 to about 12 hours at a temperature of about 40 ℃ to about 100 ℃.

Alternatively, the compound of formula H ₂ NXYZG can be prepared by reacting the compound of formula VIII with hydrogen gas at a pressure between atmospheric and 50 psi in the presence of a catalyst and a polar solvent. Suitable catalysts include palladium or platinum catalysts, preferably Adams catalysts (ie platinum oxides), or palladium absorbed on charcoal. Suitable solvents include alcoholic solvents, preferably methanol. The above-mentioned reaction may be carried out for about 30 minutes to about 6 hours at a temperature of about 20 ℃ to about 50 ℃, preferably about 23 ℃.

A compound of Formula VIII wherein Y is oxygen, sulfur, -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH ₂ [N (R ¹⁴ )]-or -SO ₂ [N (R ¹⁴ )]- Can be prepared by reacting a compound of formula X, wherein the L ⁷ group is fluoro or chloro, in the presence of a base in a silver aprotic solvent with a compound of formula IX:

G-Z-Y-H

Wherein Y is oxygen, sulfur, -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH ₂ [N (R ¹⁴ )]-or -SO ₂ [N (R ¹⁴ )]-.

Suitable bases include alkali metal hydride bases; Preferably sodium hydride is included. Suitable solvents include dimethylformamide, tetrahydrofuran or 1,2-dimethoxyethane; Preferably dimethylformamide is included. The above-mentioned reaction may be carried out for about 1 hour to about 24 hours at a temperature of about 40 ℃ to about 140 ℃, preferably about 80 ℃ to about 120 ℃.

Alternatively, Y is oxygen, sulfur, -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH ₂ [N (R ¹⁴ )]-or -SO ₂ [N (R ¹⁴ )]- The compounds of formula (VIII) described above are prepared in the presence of an alkali metal hydroxide base, preferably potassium hydroxide, in an aromatic hydrocarbon solvent, optionally in the presence of a phase transfer catalyst such as quaternary ammonium or phosphonium salts, preferably tetrabutylammonium bromide Can be prepared. Preferably the solvent is benzene or toluene. The above-mentioned reaction may be carried out for about 1 hour to about 12 hours at a temperature of about 0 ° C to about 120 ° C, preferably about 23 ° C.

Alternatively, Y is oxygen, sulfur, -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH ₂ [N (R ¹⁴ )]-or -SO ₂ [N (R ¹⁴ )]- The compounds of formula (VIII) described above may be prepared under so-called "Ulman coupling" conditions. Under these conditions, the compounds of formula (VIII) described above may be prepared by reacting a compound of formula (X), wherein the L ⁷ group is bromo or chloro, with a compound of formula (IX) in the presence of a base and a catalyst in a polar aprotic solvent Can:

<Formula IX>

G-Z-Y-H

Wherein Y is oxygen, sulfur, -CH ₂ S-, -CH ₂ O-,> NR ¹⁴ , -CH ₂ [N (R ¹⁴ )]-or -SO ₂ [N (R ¹⁴ )]-.

Suitable bases include alkali metal carbonates or hydroxide bases, preferably potassium carbonate. Suitable catalysts include copper (0) catalysts, preferably finely divided copper bronze. Suitable solvents include dimethylformamide or 1-methyl-2-pyrrolidinone. The above-mentioned reaction may be performed at a temperature of about 80 ° C. to about 140 ° C. for about 6 hours to about 24 hours.

Y group is in an oxidized state, that is,> SO ₂ ,> S = O, -CH ₂ SO-, -CH ₂ SO _2- , SO (CH ₂ ) _n -or -S0 ₂ (CH ₂ ) _n- The compounds can be prepared by reacting the corresponding compound of formula VIII, wherein the Y group is in the corresponding lower oxidation state with a suitable oxidizing agent in the solvent. The corresponding lower oxidation state for each compound of formula VIII wherein the Y group is> SO ₂ and> S═O is a compound of formula VIII wherein the Y group is S. The corresponding lower oxidation state for each compound of formula VIII wherein the Y group is —CH ₂ SO ₂ — and —CH ₂ SO— is a compound of formula VIII wherein the Y group is —CH ₂ S—. The corresponding lower oxidation state for each compound of Formula VIII _{wherein the} Y groups are —SO ₂ (CH ₂ ) _n — and —SO (CH ₂ ) _n — is that the Y group is —S— (CH ₂ ) _n —. Compound. Suitable oxidizing agents include peroxides, preferably peracetic acid or organic peroxides, preferably m-chloroperoxybenzoic acid or tert-butyl hydroperoxide. Suitable solvents include methylene chloride or alcohols such as ethanol. The above-described reaction may be performed at a temperature of about −10 ° C. to about 30 ° C. for about 1 hour to about 8 hours.

Compounds of formula (VIII) _wherein Y is —O (CH ₂ ) _n —, —S (CH ₂ ) _n — or —NR ¹⁴ (CH ₂ ) _n — are each a compound of formula X in the presence of a base in a polar aprotic solvent Wherein L ⁷ group is L ^8- (CH ₂ ) _n -and L ⁸ group is halo, such as chloro, bromo, iodo, mesyloxy (MsO) or tosyloxy (TsO), and a compound of formula IX It can be prepared by reacting:

<Formula IX>

G-Z-W-H

Wherein W group is oxygen, sulfur or -NR ¹⁴

Suitable bases include alkali metal carbonate bases, preferably potassium carbonate or cesium carbonate. Suitable solvents include dimethylformamide or tetrahydrofuran. The reaction described above may be carried out for about 1 to about 24 hours at a temperature of about 23 ° C to about 80 ° C, preferably about 20 ° C to about 50 ° C.

Compounds of formula (VIII) wherein Y is> C═O, —CH═CH— or —C≡C— are compounds of formula (X) wherein L ⁷ groups are dihydroxyborane; zinc halides such as chloride Zinc; or trialkyltin, such as tributyltin), can be prepared by reacting a compound of Formula IX:

<Formula IX>

GZYL ⁹

Wherein Y is> C═O, —CH═CH— or —C≡C—, and the L ⁹ group is halo; Preferably chloro, bromo or iodo.

Suitable catalysts include palladium or nickel catalysts, preferably tetrakis triphenyl phosphine palladium (0) (Pd (PPh ₃ ) ₄ ). Suitable solvents include toluene, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide. The above-described reaction may be performed at a temperature of about 23 ° C. to about 110 ° C. for about 1 hour to about 24 hours. This reaction can be facilitated by the presence of copper salts such as cuprous iodide or cuprous bromide.

Alternatively, compounds of formula (VIII) wherein Y is -C≡C- are formulated in the presence of a base in a solvent such as a trialkylamine base, preferably triethylamine and a palladium catalyst, preferably Pd (PPh ₃ ) ₄ . Can be prepared by reacting a compound of X, wherein L ⁷ is halo or triflate, preferably bromo or iodo, with a compound of formula

<Formula IX>

G-Z-Y-H

Suitable solvents include tetrahydrofuran or dimethylformamide. The reaction described above may be performed at a temperature of about 23 ° C. to about 60 ° C. for about 1 to about 24 hours.

Compounds of formula (VIIII) _wherein Y is —CH ₂ (CH ₂ ) _n — are compounds of formula (VIII) as described above in the presence of a palladium catalyst in a solvent at ambient pressure to about 50 psi, wherein Y is -CH = CH- or -C X—C-), and reacted with hydrogen gas. Preferably the palladium catalyst is palladium absorbed on charcoal. Suitable solvents include methanol or ethyl acetate. The above-described reaction may be performed at a temperature of about 20 ° C. to about 50 ° C. for about 1 hour to about 24 hours.

Compounds of formulas X and IX (ie, compounds of formula GZYH, GZWH or GZYL ⁹ ) are commercially available or are well known and can be prepared by methods known to those skilled in the art.

Compounds of formula I, which are basically basic, can form a wide variety of salts with various inorganic and organic acids. Such salts should be pharmaceutically acceptable for administration to animals, but in practice the compounds of formula (I) are first isolated from the reaction mixture as pharmaceutically unacceptable salts, then treated with alkaline reagents and simply converted back to the free base compound It is often desirable to subsequently convert this free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention are readily prepared by treating the base compound with a substantially equal amount of selected mineral or organic acid in a suitable aqueous solvent or a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent carefully, the desired solid salt is obtained.

The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the present invention are nontoxic acid addition salts, ie pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrates, sulfates, Bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, ethane Acid forming a salt containing sulfonate, benzenesulfonate, p-toluenesulfonic acid and palmoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)].

Compounds of formula (I) which are originally acidic may also form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, in particular sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical base used as a reagent for preparing the pharmaceutically acceptable base salt of the present invention is to form a nontoxic base salt with the compound of formula (I) described herein. Such non-toxic base salts include salts derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium. These salts can be readily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating to dryness the resulting solution, preferably under reduced pressure.

Alternatively, the salts can also be prepared by mixing together the lower alkanolic solution of the acidic compound with the desired alkali metal alkoxide and then evaporating to dryness the resulting solution in the same manner as above. In either case, it is desirable to use stoichiometric amounts of reagents to ensure complete reaction and maximum product yield.

<Biological analysis>

Compounds of Formula (I) or pharmaceutically acceptable salts thereof (hereinafter referred to as compounds of the present invention) inhibit metalloproteinases or mammalian leprolysine, resulting in the treatment of diseases characterized by metalloproteinase activity. The ability to demonstrate efficacy against is demonstrated by the following in vitro and in vivo tests.

MMP analysis

MMP-13 selectivity inhibitors are screened for inhibitors of the invention through the MMP fluorescence assay described below, wherein the MMP-13 / MMP-X inhibitory IC ₅₀ ratio, wherein MMP-X is one or more other MMPs, is 100 or more. And by selecting agents that have an efficacy of less than 100 nM.

As used herein, nonselective collagenase inhibitors, unless stated otherwise, show MMP-13 / MMP-X fluorescence assays described below, with less than 100-fold selectivity to inhibit MMP-13 enzyme activity relative to MMP-X enzyme activity. And agents with IC ₅₀ potency above 100 nM.

The ability of collagenase inhibitors to inhibit collagenase activity is well known in the art. The degree of inhibition of specific MMPs for various compounds is well documented in the art, and those skilled in the art will know how to normalize the different assay results in the assays described herein. The following assay can be used to identify matrix metalloproteinase inhibitors.

Inhibition of Human Collagenase (MMP-1)

Trypsin is used to activate human recombinant collagenase. The amount of trypsin is optimized for each collagenase-1, but a typical reaction utilizes a ratio of 5 μg trypsin per 100 μg collagenase. After trypsin and collagenase are incubated at room temperature for 10 minutes, a 5-fold excess (50 mg / trypsin 10 μg) of soy trypsin inhibitor is added.

The inhibitor stock solution (10 mM) was dissolved in dimethylsulfoxide and diluted in the following order.

10 mM ----> 120 μM ----> 12 μM ----> 1.2 μM ----> 0.12 μM

25 μl of solution at each concentration is added in triplicates to the appropriate wells of a 96 well microfluorescent plate. After addition of the enzyme and substrate, the final concentration of inhibitor will be diluted 1: 4. Positive controls (with enzyme, no inhibitor) are placed in D7-D12 wells and negative controls (no enzyme, no inhibitor) are placed in D1-D6 wells.

Dilute collagenase-1 to 240 ng / ml and add 25 μl of this solution to the appropriate wells of the microfluorescence plate. The final concentration of collagenase used for analysis is 60 ng / ml.

Substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ ) is made into 5 mM stock solution in dimethylsulfoxide and diluted to 20 μM in assay buffer. The assay is started by adding 50 μl of substrate per well of the microfluorescence plate to a final concentration of 10 μM.

Fluorescence readings (360 nm excitation, 460 nm emission) were taken at zero time and then measured every 20 minutes. The analysis was performed for 3 hours at room temperature, which is a typical analysis time.

Fluorescence versus time is plotted against a sample containing blank and collagenase (value obtained by averaging three measurement data). To measure the IC ₅₀ value, provide a good signal (more than 5 times the blank) and select a time point (usually around 120 minutes) in the linear portion of the curve. The zero time is blanked for each compound at each concentration and this value is subtracted from the data at 120 minutes. Plot data as inhibitor concentration versus control% (fluorescence value of inhibitor divided by fluorescence value of collagenase alone x 100). The concentration of the inhibitor whose signal is 50% of the control is determined by IC ₅₀ .

If the IC ₅₀ is reported to be less than 0.03 μM, the inhibitor is analyzed at concentrations of 0.3 μM, 0.03 μM and 0.003 μM.

Inhibition of Gelatinase (MMP-2)

Human recombinant 72 kD gelatinase (MMP-2, gela) gently shaking at 4 ° C. for 16-18 hours using 1 mM p-aminophenyl-mercuric acetate (from 100 mM stock solution in freshly prepared 0.2N NaOH) Activates tinase A).

10 mM dimethylsulfoxide stock of the inhibitor was added to assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl ₂ , 20 μΜ ZnCl ₂ and 0.02% BRIJ-35 (volume / volume)) using the following sequence. Dilute sequentially.

10 mM ----> 120 μM ----> 12 μM ----> 1.2 μM ----> 0.12 μM

If necessary, further dilute in the same manner as above. The minimum concentration of four inhibitors for each compound is used for each assay. 25 μl of solution at each concentration is added in triplicates to the wells of a black 96 well U-bottom microfluorescence plate. Since the final assay volume is 100 μl, the final concentration of the inhibitor is equal to the additional 1: 4 dilution result (ie 30 μM ----> 3 μM ----> 0.3 μM ----> 0.03 μM, etc.) . Blanks (no enzyme, no inhibitor) and positive enzyme controls (with enzyme, no inhibitor) are also made in duplicate.

Activated enzyme is diluted to 100 ng / ml in assay buffer and 25 μl per well is added to the appropriate wells of the microplates. The final enzyme concentration in the assay is 25 ng / ml (0.34 nM).

5 mM dimethylsulfoxide stock of substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH ₂ ) is diluted to assay buffer to 20 μM. The assay is initiated by adding 50 μl of diluted substrate so that the final assay concentration of the substrate is 10 μM. Using a PerSeptive Biosystems CytoFluor Multi-Well Plate Reader with 90 input / output ratios, fluorescence readings (320 excitation, 390 emission) are immediately obtained at zero time, followed by room temperature Measure every 15 minutes at.

The fluorescence mean of enzyme and blank is plotted against time. Select the initial time point in the linear portion of this curve for IC ₅₀ measurements. The zero time value of each compound in each dilution is subtracted from the later time value and this data is expressed as the percentage of the enzyme control (inhibitor fluorescence divided by the fluorescence of the positive enzyme control x 100). Data is plotted as a percentage of inhibitor concentration versus enzyme control. IC ₅₀ was determined as the inhibitor concentration showing 50% signal of the positive enzyme control.

Inhibition of stromelysin activity (MMP-3)

Human recombinant stromelysin (MMP-3, stromelysin-1) at 37 ° C. for 20-22 hours using 2 mM p-aminophenyl-mercuric acetate (from 100 mM stock in freshly prepared 0.2N NaOH) Activate.

The 10 mM dimethylsulfoxide stock of the inhibitor is serially diluted in assay buffer (50 mM TRIS, pH 7.5, 150 mM NaCl, 10 mM CaCl ₂ and 0.05% BRIJ-35 (volume / volume)) using the following procedure.

10 mM ----> 120 μM ----> 12 μM ----> 1.2 μM ----> 0.12 μM

If necessary, further dilute in the same manner as above. The minimum concentration of four inhibitors for each compound is used for each assay. 25 μl of solution at each concentration is added in triplicates to the wells of a black 96 well U-bottom microfluorescence plate. Since the final assay volume is 100 μl, the final concentration of the inhibitor is equal to the additional 1: 4 dilution result (ie 30 μM ----> 3 μM ----> 0.3 μM ----> 0.03 μM, etc.) . Blanks (no enzyme, no inhibitor) and positive enzyme controls (with enzyme, no inhibitor) are also made in duplicate.

Activated enzyme is diluted to 200 ng / ml in assay buffer and 25 μl per well is added to the appropriate wells of the microplates. Final enzyme concentration in the assay is 50 ng / ml (0.875 nM).

10 mM dimethylsulfoxide stock of substrate (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys (Dnp) -NH ₂ ) is diluted to assay buffer to 6 μM. The assay is initiated by adding 50 μl of diluted substrate to bring the final assay concentration of the substrate to 3 μM. Using a Perceptive Biosystems cytofluoric multi-well plate reader with an input / output ratio of 90 units, the fluorescence reading (320 excitation, 390 emission) is obtained immediately at zero time and then measured every 15 minutes at room temperature.

The fluorescence mean of enzyme and blank is plotted against time. Select the initial time point in the linear portion of this curve for IC ₅₀ measurements. The zero time value of each compound in each dilution is subtracted from the later time value and this data is expressed as the percentage of the enzyme control (inhibitor fluorescence divided by the fluorescence of the positive enzyme control x 100). Data is plotted as a percentage of inhibitor concentration versus enzyme control. IC ₅₀ was determined as the inhibitor concentration showing 50% signal of the positive enzyme control.

Inhibition of Human 92 kD Gelatinase (MMP-9)

Inhibition of 92 kD gelatinase (MMP-9) activity was performed by human collagenase (MMP-1) using Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH ₂ substrate (10 μM). Analyze under the same conditions as in inhibition.

Human recombinant 92 kD gelatinase (MMP-9, gelatinase B) was treated at 37 ° C. for 2 hours using 1 mM p-aminophenyl-mercuric acetate (from 100 mM stock solution in freshly prepared 0.2N NaOH). Activate it.

10 mM dimethylsulfoxide stock of the inhibitor was added to assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl ₂ , 20 μΜ ZnCl ₂ and 0.02% BRIJ-35 (volume / volume)) using the following sequence. Dilute sequentially.

10 mM ----> 120 μM ----> 12 μM ----> 1.2 μM ----> 0.12 μM

If necessary, further dilute in the same manner as above. The minimum concentration of four inhibitors for each compound is used for each assay. 25 μl of solution at each concentration is added in triplicates to the wells of a black 96 well U-bottom microfluorescence plate. Since the final assay volume is 100 μl, the final concentration of the inhibitor is equal to the additional 1: 4 dilution result (ie 30 μM ----> 3 μM ----> 0.3 μM ----> 0.03 μM, etc.) . Blanks (no enzyme, no inhibitor) and positive enzyme controls (with enzyme, no inhibitor) are also made in duplicate.

Activated enzyme is diluted to 100 ng / ml in assay buffer and 25 μl per well is added to the appropriate wells of the microplates. The final enzyme concentration in the assay is 25 ng / ml (0.27 nM).

5 mM dimethylsulfoxide stock of substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH ₂ ) is diluted to assay buffer to 20 μM. The assay is initiated by adding 50 μl of diluted substrate so that the final assay concentration of the substrate is 10 μM. Using a Perceptive Biosystems cytofluoric multi-well plate reader with an input / output ratio of 90 units, fluorescence readings (320 excitation, 390 emission) were immediately obtained at zero time and then measured every 15 minutes at room temperature.

The fluorescence mean of enzyme and blank is plotted against time. Select the initial time point in the linear portion of this curve for IC ₅₀ measurements. The zero time value of each compound in each dilution is subtracted from the later time value and this data is expressed as the percentage of the enzyme control (inhibitor fluorescence divided by the fluorescence of the positive enzyme control x 100). Data is plotted as a percentage of inhibitor concentration versus enzyme control. IC ₅₀ was determined as the inhibitor concentration showing 50% signal of the positive enzyme control.

Inhibition of MMP-13

After activating human recombinant MMP-13 at 37 ° C. for 1.5 hours using 2 mM APMA (p-aminophenyl-mercuric acetate), assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, Dilute to 400 mg / ml in 20 μM zinc chloride, 0.02% Brij). 25 μl of diluted enzyme is added to each well of a 96 well microfluorescence plate. Inhibitors and substrates are then added to dilute this enzyme in a 1: 4 ratio and the final concentration of the substrate used for analysis is 100 μg / ml.

10 mM stock of inhibitor is dissolved in dimethylsulfoxide and then diluted in assay buffer in the same manner as the dilution of each inhibitor in the inhibition of human collagenase (MMP-1). 25 μl of solution at each concentration is added in triplicate to the microfluorescent plate. Final concentrations in the assay are 30 μM, 3 μM, 0.3 μM and 0.03 μM.

Substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ ) was prepared as in the inhibition of human collagenase (MMP-1) and 50 μl of this substrate was prepared. Add to each well to bring the final assay concentration to 10 μM. Fluorescence readings (360 nm excitation, 450 nm emission) are obtained at zero time and measured for 1 hour at 5 minute intervals.

Positive controls consist of enzymes and substrates but no inhibitors, and blanks consist only of substrates.

IC ₅₀ is measured as in inhibition of human collagenase (MMP-1). If IC ₅₀ is reported to be less than 0.03 μM, inhibitors are analyzed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.0003 μM.

Collagen Film MMP-13 Analysis

Rat type I collagen was radiolabeled using ¹⁴ C acetic anhydride (TE Cawston and AJ Barrett, Anal. Biochem., 99, 340-345 (1979)) and used to contain radiolabeled collagen film. 96 well plates were prepared (Barbara Johnson-Wint, Anal. Biochem., 104, 175-181 (1980)). When a solution containing collagenase is added to the wells, the enzyme breaks down the insoluble collagen that has not been released and renders it soluble. Collagenase activity is directly proportional to the amount of collagen dissolved and is measured as the ratio of radioactivity released to the supernatant, as measured on a standard scintillation meter. Thus, collagenase inhibitors are compounds that reduce the level of released radioactivity when compared to a control without the inhibitor. One specific embodiment of this analysis is described in detail below.

The following method is used to determine the selectivity of a compound for MMP-13 to MMP-1 using collagen as a substrate. Recombinant human progenitor MMP-13 or progenitor MMP-1 is activated by the method outlined above. Activated MMP-13 or MMP-1 was 0.6 μg / using buffer (50 mM Tris pH 7.5, 150 mM NaCl, 10 mM CaCl ₂ , 1 μM ZnCl ₂ , 0.05% Brij-35, 0.02% sodium azide) Dilute to ml.

A stock of test compound (10 mM) in dimethylsulfoxide is prepared. Dilute test compounds in Tris buffer above to 0.2, 2.0, 20, 200, 2000 and 20000 nM.

100 μl of the appropriate drug dilution and 100 μl of diluted enzyme are pipetted into a well of a 96 well plate containing a collagen film labeled with ¹⁴ C-collagen. Final enzyme concentration is 0.3 μg / ml, while final drug concentrations are 0.1, 1.0, 10, 100, 1000 nM. Each drug concentration and control is analyzed in triplicates. Three control groups are also performed under the condition that no enzyme is present, and when there are enzymes, it is conducted under the condition that no compound is present.

The plates are incubated at 37 ° C. for a time at which about 30-50% of the available collagen is dissolved (measured by counting additional control wells at various time points). In most cases, nine hours of incubation is required. If the analysis proceeds sufficiently, the supernatant of each well is collected and counted on a scintillation meter. Background values (measured in the wells without enzymes) are subtracted from the values in each sample and the percent release is calculated as compared to wells without enzymes only and no inhibitors. The three values for each point are averaged to graph this data as percent release versus drug concentration. IC ₅₀ is measured in that the release of radiolabeled collagen is inhibited by 50%.

To identify the active collagenase in the cartilage conditioning medium, the assay was carried out using collagen as a substrate, using cartilage conditioning medium containing collagenase activity, and inhibitors with various selectivities. Cartilage conditioning media was harvested during collagen degradation, thus representing collagenase involved in collagen breakdown. The same analysis as described above was performed except that cartilage conditioning medium was used as the enzyme source instead of using recombinant MMP-13 or recombinant MMP-1.

IL-1 Induced Cartilage Collagen Degradation in the Nasal Cartilage of Bovine

This assay uses bovine nasal cartilage ex vivo grafts primarily used to test the efficacy of various compounds that inhibit IL-1 induced proteoglycan degradation or IL-1 induced collagen degradation. Bovine nasal cartilage is a tissue very similar to articular cartilage, ie, chondrocytes surrounded mainly by a collagen and aggrecan matrix of type II. The reason for using this tissue is that it is (1) very similar to articular cartilage, (2) easy to obtain, (3) relatively homogeneous, and (4) degrades at predictable reaction rates after IL-1 stimulation.

This assay was modified in two ways and used for the analytical compound. Both variants yielded similar data. Both variants are described below:

Variant 1

Three plugs of bovine nasal cartilage (approximately 2 mm diameter x 1.5 mm long) are placed in each well of a 24-well tissue culture plate. Then 1 ml of serum free medium is added to each well. Compounds are prepared in 10 mM stock in DMSO and then diluted appropriately in serum-free medium to final concentrations of, for example, 50, 500 and 5000 nM. Analyze three batches at each concentration.

Human recombinant IL-1α (5 ng / mL) (IL-1) is added to each well containing three control wells and drug. Three control wells without both drug and IL-1 were also prepared. The medium is harvested and fresh medium of appropriate drug concentration containing IL-1 is added on days 6, 12, 18 and 24, or every 3-4 days if necessary. Media collected at each time point is stored at -20 ° C for later analysis. If the cartilage in the well containing only IL-1 is almost completely reabsorbed (about 21 days), the experiment is terminated. Collect and store this medium. At each time point, aliquots (100 μl) from each well are collected and digested with papain and analyzed for hydroxyproline content. The hydroxyproline background value (mean of wells without both IL-1 and drug) is subtracted from each data value and the mean is calculated for each of the three values. This data is expressed as a percentage of the mean of those containing only IL-1 and plotted. IC ₅₀ is calculated from this plot.

Variant 2

This test method is as outlined in the modification 1 until the 12th day. On day 12, the conditioning medium is collected and frozen in each well. 1 ml of phosphate buffered saline (PBS) containing 0.5 μg / ml trypsin is added to each well and incubated at 37 ° C. for a further 48 hours. 48 hours after incubation in trypsin, the PBS solution is collected. PBS / trypsin solution and aliquots (50 μl) at these two time points (6 and 12 days) are pooled, hydrolyzed and the hydroxyproline content is measured. The hydroxyproline background value (mean of wells without both IL-1 and drug) is subtracted from each data value and the mean is calculated for each of the three values. This data is then displayed and plotted as a percentage of the mean value of that containing only IL-1. IC ₅₀ is measured from this plot. This variant significantly reduces the time required for the experiment. When trypsin is added for 48 hours 12 days after IL-1 stimulation, any type II collagen damaged due to collagenase activity is released but not in the cartilage matrix. In the absence of IL-1 stimulation, trypsin treatment results in very low background levels of collagen degradation in cartilage explants.

Suppression of TNF Production

The presence or absence of the ability of a compound of the invention or a pharmaceutically acceptable salt thereof to inhibit the production of TNF is demonstrated by the following in vitro assay:

Human Monocyte Analysis

Human monocytes were isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation technique. Monocytes were washed three times in Hanks' equilibrium salt solution (HBSS) with divalent cations and resuspended to a density of 2 × 10 ⁶ / ml in HBSS containing 1% BSA. Differences measured using an Abbott Cell Dyn 3500 analyzer indicated that 17-24% of the total cells in this preparation were monocytes.

180 μl of cell suspension was aliquoted and placed in a flat bottom 96 well plate (Costar). Compound and LPS (final concentration 100 ng / ml) were added to a final volume of 200 μl. Three runs were performed for all conditions. After 4 hours incubation at 37 ° C. in a wet CO ₂ incubator, the plates were harvested and centrifuged (approximately 10 minutes at 250 × g), the supernatants were collected and analyzed for TNF-α using the R & D ELISA kit. It was.

Aggrecanase analysis

After sequential digestion of trypsin and collagenase, collagenase was digested overnight to isolate primary porcine cartilage cells obtained from articular cartilage and 5 μCi / ml ³⁵ S (1000 Ci / mmol) in type I collagen coated plates. Apply 2 x 10 ⁵ cells per well to a 48 well plate with sulfur. The label is allowed to be incorporated into the proteoglycan matrix of the cells (for about one week) under an atmosphere of 37 ° C., 5% CO ₂ .

The night before starting the assay, chondrocyte monolayers are washed twice in DMEM / 1% PSF / G and incubated overnight in fresh DMEM / 1% FBS.

The next morning, the chondrocytes are washed once in DMEM / 1% PSF / G. Allow the final wash to settle on the plate in the incubator while making the diluent.

Media and dilutions can be prepared as described in the table below.

Control badge DMEM only (control badge) IL-1 medium DMEM + IL-1 (5 ng / ml) Drug diluent All compounds are prepared to be 10 mM stock in DMSO. 100 μM stock of each compound in DMEM is placed in a 96 well plate. Store overnight in the refrigerator. The following day, 5 μM, 500 nM using IL-1. And serial dilution in DMEM to 50 nM. Remove the final washes from the wells and add 50 μl of the compound in the dilution to 450 μl of IL-1 medium in the appropriate well of a 48 well plate. nM, 50 nM and 5 nM. All samples are made three on each plate with control and IL-1 alone samples.

Label the plate and use only the inner 24 wells of the plate. In one of these plates, several columns are labeled IL-1 (no drug) and control (no IL-1, no drug). This control column is periodically measured to confirm 35S-proteoglycan release. Control and IL-1 medium are added to wells (450 μl) followed by the addition of compounds (50 μl) to initiate the assay. Plates are incubated under 37 ° C., 5% CO ₂ atmosphere.

The assay is terminated (9-12 hours) at 40-50% release (when CPM obtained in IL-1 medium is 4-5 times the control medium) by liquid scintillation measurement (LSC) of the medium sample. Media is collected from all wells and placed in scintillation tubes. Add scintillation and obtain radioactivity value (LSC). To lyse the cell layer, 500 μl of papain digestion buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT, and 1 mg / ml papain) is added to each well. Plates with degradation solution are incubated overnight at 60 ° C. The next day, the cell layer is harvested from this plate and placed in a scintillation tube. After addition of the scintillation, the sample is measured (LSC).

The percentage of released number relative to the total number present in each well is measured. Three wells are obtained by subtracting the control background from each well. Compound inhibition is based on IL-1 samples as 0% inhibition (total 100%).

The compounds of the invention tested in one or more of these assays all had IC _50s of less than 100 μM, preferably less than 100 nM. Preferred compounds have certain selectivity in certain groups for various MMPs or ADAMs. One group of preferred compounds has selective activity against MMP-13 over MMP-1. One group of preferred compounds has selective activity against MMP-13 over MMP-1, MMP-3 and MMP-7. One group of preferred compounds has selective activity against MMP-13 over MMP-1, MMP-3, MMP-7 and MMP-17. One group of preferred compounds has selective activity against MMP-13 over MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and MMP-14. Another group of preferred compounds have selective activity against MMP-13 over MMP-12 and MMP-14.

When administered to mammals, including humans, for the inhibition of matrix metalloproteinases or mammalian leprolysine, there are a variety of conventional methods including oral, parenteral (eg, intravenous, intramuscular or subcutaneous), buccal, anal and topical. Can be used. In general, the compounds of the present invention (hereinafter also referred to as active compounds) are administered at a dosage of about 0.1 to 25 mg, preferably 0.3 to 5 mg per kg body weight of the subject to be treated per day. Preferably the active compound is administered orally or parenterally. However, there may be some changes in dosage depending on the condition of the subject to be treated. The administering person will determine the appropriate dosage for the individual subject in any event.

The compounds of the present invention can be administered in a wide variety of different dosage forms, and in general, compounds effective for the treatment of the present invention are present at concentration levels of about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be prepared, such as starch (preferably corn, potato or tapioca starch), alginic acid and some complex silicates. Various disintegrants and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia can be used. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules, and preferred materials in this context include high molecular weight polyethylene glycols as well as lactose or lactose. If aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be formulated with various sweetening or flavoring agents, coloring materials or pigments, and optionally emulsifiers and / or suspending agents, as well as water, ethanol, propylene glycol, glycerin And diluents such as various mixtures thereof. In the case of animals, they are advantageously contained in animal feed or beverages at concentrations of 5 to 5000 ppm, preferably 25 to 500 ppm.

For parenteral administration (muscular, intraperitoneal, subcutaneous and intravenous use) according to the invention, injectable sterile solutions of the active ingredient are usually prepared. Solutions of the therapeutic compounds of the invention in sesame oil or peanut oil, or aqueous propylene glycol can be used. The aqueous solution must be properly adjusted and buffered, if necessary, preferably a pH greater than 8, and the liquid diluent must first be isotonic. Such aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of both of these solutions under sterile conditions can be readily accomplished by standard pharmaceutical techniques known to those skilled in the art. In animals, the compound may be administered intramuscularly or subcutaneously at a dosage of 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day, in one or three doses.

The active compounds described herein may also be formulated into rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the present invention may be in the form of solutions or suspensions from pump injection vessels squeezed or pumped by the patient, or with suitable propellants such as dichlorodifluoromethane, trichloro It is readily delivered in the form of an aerosol propellant from a compressed vessel or sprayer using fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a compressed aerosol, the dosage unit can be determined by providing a valve to deliver a quantified amount. Compressed containers and nebulizers can include solutions or suspensions of the active compounds. Capsules and cartridges (eg, made of gelatin) for inhaler or insufflator use may be formulated containing a mixture of a compound of the invention with a suitable powder based powder mixture such as lactose or starch.

For topical ocular administration, it may be applied directly to the developing eye in the form of preparations such as eye drops, aerosols, gels or ointments, or collagen (eg poly-2-hydroxyethylmethacrylate and copolymers thereof) or hydrophilic polymers Can be incorporated into the shield. The material may also be added as a contact lens or via a local reservoir or as a subconjunctival preparation.

For orbital administration, it is usually prepared as a sterile injectable solution of the active ingredient. Solutions of the therapeutic compounds of the invention (particle sizes less than 10 microns) in aqueous solutions or suspensions can be used. Suitably, the aqueous solution should be adjusted and buffered, preferably to pH 5-8, as needed, and the liquid diluent first to be isotonic. Small amounts of polymers (eg, cellulose polymers, dextran, polyethylene glycol, or alginic acid) may be added to increase viscosity or allow sustained release. Such solutions are suitable for intraocular injection purposes. The preparation of all such solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For animals, the compound can be administered intraorbitally in one or three divided doses at a dose of about 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day.

For other routes of administration and corresponding dosage forms described herein, the dosage forms intended for oral administration are also suitably formulated to provide controlled, sustained release and / or delayed release of the active ingredient. Typically, these include delayed release oral tablets, capsules, and multiparticulates, as well as inhibiting the release and absorption of the active ingredient in the stomach of the patient, which promotes intestinal delivery to the terminal of the stomach, ie to the small intestine. Enteric coated tablets and capsules. Other typical oral dosage forms include sustained release oral tablets, capsules, and multiparticulates that allow the active ingredient to be delivered systemically in a controlled manner over long periods of time, such as 24 hours. If rapid delivery of the active ingredient is required or desired, a controlled release oral dosage form can be prepared in the form of a rapid dissolving tablet, preferably comprising a highly soluble salt form of the active ingredient.

The following examples illustrate the preparation of the compounds of the present invention. Melting point was not corrected. NMR data are reported in ppm (δ) and refer to the deuterium lock signal from the sample solvent (unless otherwise stated deuterium chloroform). Commercially available reagents were used without further purification. Chromatography refers to column chromatography using 32-63 mm silica gel and performed under nitrogen pressure (flash chromatography) conditions. Room temperature or ambient temperature represents 20-25 ° C. All non-aqueous reactions are carried out under nitrogen atmosphere for convenience in order to maximize yield. Decompression or vacuum concentration means using a rotary evaporator.

General experiment

General Example:

The compound of formula (I) is prepared at a temperature of 20 ° C. to the boiling point of the solvent, preferably 80 ° C. in the presence of a suitable base such as an alkoxide base, preferably sodium ethoxide, in a polar solvent such as an alcoholic solvent, preferably ethanol. A suitable compound of formula III can be prepared by reacting with a urea of formula II (ie H ₂ N (CO) -NH ₂ ) for 15 minutes to 3 hours.

General manufacturing example:

Compounds of formula (III) are suitable bases with suitable bases of compounds of formula (IV) for about 6 to about 36 hours at temperatures of from about 0 ° C. to about 50 ° C., preferably about 20 ° C. in polar solvents such as alcoholic solvents, preferably ethanol. For example, by reacting with a tertiary amine base or a polymer bound base, preferably Amberlyst-400® resin (in hydroxide form).

The compound of formula (IV) may be prepared in an aprotic solvent and preferably in an aromatic hydrocarbon solvent such as benzene or toluene for about 1 to about 6 hours at a temperature of about 40 ° C. to the boiling point of the solvent, preferably about 80 ° C. The compound may be prepared by reacting with a compound of formula V or V 'wherein the formula is L ^3- (A')-L ⁴ or L ^3- (A ').

The compound of formula VI is for about 4 to about 48 hours at a temperature of about 20 ° C. to about 100 ° C., preferably about 80 ° C. in the presence of a suitable base such as a tertiary amine base, preferably N, N-dimethylaniline. It can be prepared by reacting a suitable compound of formula NH ₂ -XYZG with a compound of formula VII which is a 2-halo malonate ester, preferably _2- bromodiethyl malonate.

Example 1:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane-2,6,8,10-tetraone:

Sodium metal (29 mg, 1.26 mmol) was added to 1.3 ml of ethanol, stirred until homogenized and 1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -pyrrolidine- 2,2-dicarboxylic acid diethyl ester (0.20 g, 0.42 mmol) was added, followed by urea (75 mg, 1.26 mmol) and the mixture was stirred at 80 ° C for 5 minutes. The mixture was cooled to ambient temperature, acidified with 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (3: 1 hexane-ethyl acetate) to give 1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro 28 mg of [4,5] decane-2,6,8,10-tetraone were obtained as a colorless solid.

Preparation Example 1:

2- (4-Bromo-phenoxy) -5-nitro-pyridine:

4-bromophenol (5.5 g, 32 mmol) was added to 42 ml of 50% (w / w) aqueous sodium hydroxide. After stirring for 30 minutes, 44 ml of toluene was added followed by 2-chloro-5-nitropyridine (5.0 g, 32 mmol) and tetrabutylammonium bromide (10 g, 32 mmol). After stirring at 23 ° C. for 1.5 h, the mixture was diluted with 200 ml of water, neutralized with 12M aqueous hydrochloric acid and the mixture was extracted three times with ether. The combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo, and 6 g of 2- (4-bromo-phenoxy) -5-nitro-pyridine was obtained.

6- (4-Bromo-phenoxy) -pyridin-3-ylamine:

A mixture of 2- (4-bromo-phenoxy) -5-nitro-pyridine (6.0 g, 22.7 mmol), 200 ml of methanol and 50 mg of PtO ₂ was shaken at 23 ° C. for 1 hour under 50 psi of H ₂ . The mixture was filtered through a pad of Celite®, the filtrate was concentrated in vacuo and 6 g of 6- (4-bromo-phenoxy) -pyridin-3-ylamine was obtained.

Preparation Example 2:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester:

6- (4-bromo-phenoxy) -pyridin-3-ylamine (4.5 g, 16.9 mmol), 2-bromodimethylmalonate (4.1 g, 17 mmol) and N, N-dimethylaniline (2.1 g , 17 mmol) was stirred at 80 ° C for 24 h. The mixture was cooled to 23 ° C., diluted with 50 ml of benzene and treated with 7 ml of 2-bromopropionyl chloride. After stirring for 3 hours at reflux, the mixture was cooled to 23 ° C, concentrated in vacuo and diluted with 750 ml of ethanol. Amberlyst-400 (hydroxide form) resin (75 g) was added and the mixture was stirred at 23 ° C for 24 h. The mixture was filtered and the resin washed with 50 ml of methanol. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (2: 1 hexane-ethyl acetate) to give 1- [6- (4-bromo-phenoxy) -pyridin-3-yl] -pyrrolidine- 6 g of 2,2-dicarboxylic acid diethyl ester were obtained.

The following compounds were prepared according to methods analogous to those of Example 1 by optionally replacing appropriate pyridine and diesters:

Example 4

4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzonitrile:

1- [6- (4-cyano-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid according to the procedure for pyrimidinetrione formation described in Example 1 Diethyl ester (58 mg, 0.14 mmol) was reacted with urea (0.030 g, 0.5 mmol) in 0.5 ml of 1 M sodium ethoxide in ethanol to 4- [5- (2,6,8,10-tetraoxo-1 14.3 mg of 7,7,9-triaza-spiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzonitrile was obtained as a colorless solid.

Preparation Example 1:

1- [6- (4-Cyano-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.28 g, 0.53 mmol), zinc cyanide (0.037 g , 0.32 mmol), tetrakistriphenylphosphine palladium (0) (0.024 g, 0.021 mmol) and 0.66 ml of dimethylformamide were heated to 80 ° C for 24 h. Further 37 mg zinc cyanide and 24 mg tetrakistriphenylphosphine palladium (0) were added and the mixture was stirred at 80 ° C. for a further 48 h. After cooling to room temperature, the mixture was diluted with toluene, washed with 2M ammonium hydroxide (twice), brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by radial chromatography (ethyl acetate-hexane, then methanol) yields 1- [6- (4-cyano-phenoxy) -pyridin-3-yl] pyrrolidine-2,2-dicarboxylic acid diethyl 58 mg of ester were obtained as a colorless syrup.

Example 5

1- [6- [4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane -2,6,8,10-tetraon:

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl]-, according to the procedure for pyrimidinetrione formation described in Example 1 5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (200 mg, 0.44 mmol) was reacted with urea (0.080 g, 1.3 mmol) in 1.3 ml of 1 M sodium ethoxide in ethanol to give 1- [ 6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane-2, 25 mg of 6,8,10-tetraone were obtained as a colorless solid.

Preparation Example 1:

1- [6- (4-carboxy-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.70 g, 1.64 mmol), sodium carbonate (0.26 g, 1.64 mmol) and 16.4 ml of tert-butyl alcohol-water (1: 1) were treated with potassium permanganate (0.26 g, 1.64 mmol). After stirring for 2 hours at room temperature, the mixture was quenched with sodium sulfite, acidified with 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to 1- [6- (4-carboxy-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxyl Acid diethyl ester (0.5 g) was obtained as a colorless syrup.

Preparation Example 2:

1- [6- (4-Hydrazinocarbonyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester:

Obtained 1- [6- (4-carboxy-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.4 g, 0.97 mmol), A mixture of 1-hydroxybenzotriazole hydrate (0.176 g, 1.3 mmol), 1,2-dichloroethane (0.25 g, 1.3 mmol) and 6 ml of methylene chloride was stirred at room temperature for 20 minutes. The mixture was treated with boc-hydrazide (0.17 g, 1.3 mmol) and stirred at rt overnight. The mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 5 ml of methylene chloride-trifluoroacetic acid (1: 1 v / v), stirred at ambient temperature for 1 hour and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated to 1- [6- (4-hydrazinocarbonyl-phenoxy) -pyridin-3-yl] -5-Oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g) was obtained as a colorless syrup. HPLC: 2.770 min.

Preparation Example 3:

1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid Diethyl ester:

Obtained 1- [6- (4-hydrazinocarbonyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol), trimethylorthoformate (0.1 ml, 0.91 mmol) and 1 ml of xylene were refluxed for 24 h. The mixture was concentrated in vacuo to give 1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2 -Dicarboxylic acid diethyl ester (0.2 g) was obtained as a colorless syrup. MS (APCI, m / z): 467.2 [M + H] ⁺ .

Example 6

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane-2,6,8,10-tetraone:

1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dica according to the procedure for pyrimidinetrione formation described in Example 1 Reacidic diethyl ester (200 mg, 0.41 mmol) was reacted with urea (0.088 g, 1.4 mmol) in 1.4 ml of 1 M sodium ethoxide in ethanol to give 1- [6- (4- [1,3,4] oxa Diazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane-2,6,8,10-tetraone 25 mg colorless solid Obtained as

Preparation Example 1:

1- [6- (4-Ethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-Vinyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g), 50 mg 10% palladium on charcoal and ethyl A mixture of 20 ml of acetate was shaken for 2 hours under 50 psi of hydrogen gas. The mixture was filtered and concentrated in vacuo to give 0.20 g of 1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester Was obtained as a colorless syrup.

Example 7

N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4,5] dec-1-yl) -pyridin-2-yloxy]- Benzyl} -acetamide:

1- {6- [4- (tert-Butoxycarbonylamino-methyl) -phenoxy] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.52 mmol) And a mixture of 2 ml of a solution of trifluoroacetic acid (1: 1 v / v) in methylene chloride was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in 2.6 ml of methylene chloride, treated with MMP-resin (polymer bound N-methyl morpholine base, 0.86 g, 1.75 mmol) and treated with acetyl chloride (0.055 g, 0.7 mmol). After shaking for 24 hours, the mixture was filtered and the resin washed with methylene chloride. The combined filtrates were concentrated in vacuo, dissolved in 1.5 ml of 1 M sodium ethoxide in ethanol and treated with 94 mg of urea. After stirring at 80 ° C. for 10 minutes, the mixture was treated with 2 g of polystyrene-linked sulfonic acid resin, filtered and the resin washed with 10 ml of 2M ammonia in methanol. The combined filtrates were concentrated in vacuo, purified by reverse phase chromatography (acetonitrile-water-trifluoroacetic acid eluent) and then by radial chromatography (10% methanol-methylene chloride) to give N- {4- [5- ( 2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4,5] dec-1-yl) -pyridin-2-yloxy] -benzyl} -acetamide as a colorless solid Obtained. HPLC retention time: 2.201 minutes; MS (APCI, m / z): 436 [M ⁻ H] ⁻ ; 438 [M + H] ⁺ .

Preparation Example 1:

1- [6- (4-Vinyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-Bromo-phenoxy) -pyridin-3-yl) -pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.8 g, 12.2 mmol), vinyltributyltin ( 3.9 ml, 12.3 mmol), tetrakistriphenylphosphine palladium (0) (0.60 g, 0.52 mmol) and 24 ml of toluene were heated to reflux for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and purified by silica gel chromatography (flash 40, 20% to 50% ethyl acetate-hexane) to give 1- [6- (4-vinyl-phenoxy) -pyridine-3 4.8 g of -yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester were obtained as a colorless syrup.

Preparation Example 2:

1- [6- (4-Formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-Vinyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (4.8 g, 11.3 mmol), sodium metaperiodate ( 4.8 g, 22 mmol), a mixture of osmium tetraoxide (10 mg) and dioxane-water (2: 1; 189 ml) were stirred at ambient temperature for 6 hours. The mixture was quenched with sodium sulfite, diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to 1- [6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl Ester (4.6 g) was obtained as a colorless syrup.

Preparation Example 3:

1- {6- [4- (tert-Butoxycarbonylamino-methyl) -phenoxy] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.1 g, 0.24 mmol), tert-butoxycar A mixture of bonylamide (0.083 g, 0.71 mmol), triethylsilane (0.11 ml, 0.083 g, 0.71 mmol) and acetonitrile (1 ml) was treated with trifluoroacetic acid (0.035 ml, 0.46 mmol) and 48 hours Stirred at ambient temperature. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1- {6- [4- (tert-butoxycarbonylamino-methyl)- Phenoxy] -pyridin-3-yl} -pyrrolidine-2,2-dicarboxylic acid diethyl ester was obtained as a colorless syrup.

The following compounds were prepared according to methods analogous to those of Example 7 by optionally replacing appropriate pyridine and diesters:

Example 12

1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane-2,6,8, 10-tetraon:

5-oxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -pyrrolidine according to the procedure for pyrimidinetrione formation described in Example 1 -2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mol) was reacted with urea (0.074 g, 1.2 mmol) in 1.2 ml of 1 M sodium ethoxide in ethanol to give 1- [6- (4-pyra). Zol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4,5] decane-2,6,8,10-tetraone 6 mg colorless solid Obtained as

Preparation Example 1:

1- [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester: 1- [in 30 ml of ethanol Sodium borohydride (0.090 g) in a solution of 6- (4-formyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester (1.0 g, 2.3 mmol) , 2.3 mmol) was added at 0 ° C. After stirring for 3 hours, the mixture was concentrated in vacuo, diluted with ethyl acetate and water, the aqueous layer carefully acidified with 1M hydrochloric acid and then neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1- [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo 0.80 g (80% of -pyrrolidine-2,2-dicarboxylic acid diethyl ester was obtained as a colorless syrup.

Preparation Example 2:

1- [6- (4-Bromomethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-hydroxymethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester in 9.4 ml of methylene chloride (0.80 g , 1.9 mmol) was added triethylamine (0.46 ml, 0.33 g, 3.3 ml). After cooling to -40 ° C, the mixture was treated with methanesulfonyl chloride (0.20 ml, 0.30 g, 2.61 mmol). After stirring for 1 hour, further 0.10 ml of methanesulfonyl chloride and 0.4 ml of triethylamine were added and stirring was continued for 1 hour. A solution of anhydrous lithium bromide (1.6 g, 19 mmol, flame dried in vacuo before use) in tetrahydrofuran (20 ml) was added via cannula and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate and the organic phase was washed with water, dried over sodium sulphate, filtered and concentrated in vacuo. Eluted with ethyl acetate-hexane (1: 1) and the residue was filtered through a pad of silica gel to give 1- [6- (4-bromomethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrroli 0.65 g of dean-2,2-dicarboxylic acid diethyl ester were obtained as colorless syrup.

Preparation Example 3:

5-Oxo-1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -pyrrolidine-2,2-dicarboxylic acid diethyl ester:

1- [6- (4-Bromomethyl-phenoxy) -pyridin-3-yl] -5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 in 0.8 ml of dimethylformamide) g, 0.4 mmol) was added pyrazole (0.056 g, 0.82 mm) and potassium carbonate (0.11 g, 0.82 mmol). After stirring at 50 ° C. for 24 h, the mixture is diluted with water, extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo to give the crude product as a colorless syrup, the next step Used immediately.

MS (APCI, m / z): 479.2 [M + H] ⁺ .

While the invention has been described and described with reference to specific embodiments thereof, those skilled in the art will recognize that various manipulations, changes, alterations, substitutions, removals or additions of the procedures and protocols may be made without departing from the spirit and scope of the invention. will be. In the case of an embodiment, effective doses other than the specific doses described above may be applied as changes in the response of the mammal to be treated for any symptom using the compounds of the invention described above. Likewise, the specific pharmacological response observed may vary depending on the presence of the particular active compound or pharmaceutical carrier selected, as well as the type of formulation and the mode of administration used, as a result of which such expected changes or differences may occur. It is considered according to the purpose and practice. Accordingly, the invention is defined by the scope of the following claims, which should be interpreted broadly and justly.

Claims (11)

Compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Wherein "A" is a 5-7 membered heterocyclic ring selected from the group consisting of Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are hydrogen, (C _1- C ₄ ) alkyl, (C ₁ -C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) Cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl, each independently selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C _1- C ₁₀ ) heteroaryl, (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl are halo, (C ₁ -C ₄ ) alkyl, on a ring carbon atom which may form additional bonds, Optionally substituted 1 to 3 times per ring by a substituent independently selected from (C ₁ -C ₄ ) alkoxy, —CN, —OH and —NH ₂ ; X is (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₁₀ ) heteroaryl; Y is a bond, oxygen, sulfur,> C = O,> SO ₂ ,> S = O, -CH _2- , -CH ₂ O-, -O (CH ₂ ) _n- , -CH ₂ S-, -S (CH ₂ ) _n- , -CH ₂ SO-, -CH ₂ SO _2- , -SO (CH ₂ ) _n- , -SO ₂ (CH ₂ ) _n- , -NR ¹⁴ , -NR ¹⁴ (CH ₂ ) _n- , -CH ₂ [N (R ¹⁴ )]-, -CH ₂ (CH ₂ ) _n- , -CH = CH-, -C≡C-,-[N (R ¹⁴ )]-SO ₂ -and -S0 ₂ [N (R ¹⁴ )]-is selected from the group consisting of; n is an integer from 1 to 4; R ¹⁴ is hydrogen or (C ₁ -C ₄ ) alkyl; Z is selected from the group consisting of (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heterocyclyl and (C ₁ -C ₁₀ ) heteroaryl , One or two carbon-carbon single bonds of (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₁₀ ) heterocyclyl may be optionally replaced with a carbon-carbon double bond, Each of X or Z is independently F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl on a ring carbon atom capable of forming additional bonds Optionally substituted one or two times per ring by a substituent independently selected from (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy and (C ₃ -C ₈ ) cycloalkyloxy ; G is R ^15- (CR ¹⁶ R ¹⁷ ) _p- , where G is a substituent on a ring carbon atom of Z that can form additional bonds, excluding the alpha position relative to the point of attachment of the Z ring and Y Oriented in position; p is an integer from 0 to 4; R ¹⁵ is halo, —CN, —NO ₂ , OH, (C ₁ -C ₄ ) alkenyl, (C ₁ -C ₄ ) alkynyl, (C ₁ -C ₄ ) perfluoroalkyl, perfluoro ( C ₁ -C ₄ ) alkoxy, R ^18- , R ¹⁸ -O-, R ^18- (C ₁ -C ₄ ) alkyl-O-, R ^18- (C = O)-, R ^18- (C = O ) -O-, R ¹⁸ -O- (C = O)-, R ¹⁸ -S-, R ^22- (S = O)-, R ^18- (SO ₂ )-, R ^22- (SO ₂ )- (NR ²¹ )-, R ^19- (C = O)-(NR ²¹ )-, R ²² -O- (C = O)-(NR ²¹ )-, (R ¹⁹ R ²⁰ ) N-, (R ¹⁹ R ²⁰ ) N- (SO ₂ )-, (R ¹⁹ R ²⁰ ) N- (C = O)-, (R ¹⁹ R ²⁰ ) N- (C = O)-(NR ²¹ )-and (R ¹⁹ R ²⁰ ) N- (C═O) —O— is independently selected from the group consisting of; Each of R ¹⁶ and R ¹⁷ is independently selected from hydrogen and (C ₁ -C ₄ ) alkyl, or Or R ¹⁶ and R ¹⁷ can optionally form a 5 to 10 membered carbocyclic ring with the carbon atom to which they are attached; R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are hydrogen, (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) hetero Independently selected from the group consisting of aryl and (C ₁ -C ₁₀ ) heterocyclyl, wherein (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) Heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties are F, Cl, Br, CN, OH, (C ₁ -C ₄ ) alkyl, (C _1- ) on ring carbon atoms that can form additional bonds C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) Alkyl] may be optionally substituted 1 to 3 per ring by a substituent independently selected from ₂ -N- and (C ₃ -C ₈ ) cycloalkyloxy, wherein the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀₎ heterocyclyl moieties may also be optionally substituted by oxo, it said (C ₁ -C ₁₀₎ heteroaryl and (C ₁ -C ₁₀₎ heterocyclyl residues are weight On ring nitrogen atoms which may have a substituent (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ alkyl - (C = O) - 1 to 2 times per ring by substituents independently selected from the group consisting of May be optionally substituted; Or R ¹⁹ and R ²⁰ may optionally form a 3-8 membered heterocyclic ring with the nitrogen to which they are attached; Or R ¹⁹ and R ²¹ may optionally form a 3-8 membered heterocyclic ring with the nitrogen, carbon or oxygen to which they are attached; R ²² is (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocycle It is selected from the group consisting of, wherein said (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₁₀ ) heteroaryl and (C ₁ -C ₁₀ ) heterocyclyl moieties on ring carbon atoms capable of forming an additive combination of F, Cl, Br, CN, OH, (C 1 -C 4) alkyl, (C ₁ -C ₄₎ perfluoroalkyl, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) alkoxy, amino, (C ₁ -C ₄ ) alkyl-NH-, [(C ₁ -C ₄ ) alkyl] ₂ -N- and (C ₃ -C ₈ ) may be optionally substituted 1 to 3 per ring by a substituent independently selected from cycloalkyloxy, wherein the (C ₃ -C ₈ ) cycloalkyl and (C ₁ -C ₁₀ ) heterocyclyl moiety are also present in oxo by optionally may be substituted, the (C ₁ -C ₁₀₎ heteroaryl and (C ₁ -C ₁₀₎ heterocyclyl residues are ring which may be further have a substituent group (C ₁ -C ₄₎ alkyl and (C ₁ -C ₄₎ alkyl on the atom - (C = O) - group may be independently substituted one to two times per ring which are selected from the substituents consisting of or; Alternatively, R ²¹ and R ²² may optionally form a 3-8 membered heterocyclic ring with the nitrogen, oxygen or sulfur to which they are attached. The compound of claim 1, wherein “A” is selected from the group consisting of j) to l) below. The compound of claim 1, wherein X is (C ₆ -C ₁₀ ) aryl. The compound of claim 1, wherein X is (C ₁ -C ₁₀ ) heteroaryl. The compound of claim 1, wherein Y is oxygen. The compound of claim 1, wherein G is R ^15- (CR ¹⁶ R ¹⁷ ) _p -and p is 0. 3. The compound of claim 1, wherein G is R ^15- (CR ¹⁶ R ¹⁷ ) _p − and p is an integer from 1 to 4. 6. The method of claim 1, 1- [6- (4-fluoro-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone; 1- [6- (4-fluoro-phenoxy) -pyridin-3-yl] -1,8,10-triaza-spiro [5.5] undecane-2,7,9,11-tetraone; 4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy) -benzonitrile; 1- [6- (4- [1,3,4] oxadiazol-2-yl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2 , 6,8,10-tetraone; 1- [6- (4-ethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5Jdecane-2,6,8,10-tetraone; N- [4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} Acetamide; N- [4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} Propionamide; N- {4- [5- (2,6,8,10-Tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzyl} Butyramide; Pentanic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl) -pyridin-2-yloxy] -benzylamide; Cyclobutanecarboxylic acid 4- [5- (2,6,8,10-tetraoxo-1,7,9-triaza-spiro [4.5] dec-1-yl} -pyridin-2-yloxy]- Benzylamide; 1- [6- (4-Bromo-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10-tetraone; 1- [6- (4-pyrazol-1-ylmethyl-phenoxy) -pyridin-3-yl] -1,7,9-triaza-spiro [4.5] decane-2,6,8,10- Tetraon Compounds selected from the group consisting of: and pharmaceutically acceptable salts thereof. Connective tissue disease, inflammatory disease, immune / allergic disease, infectious disease, respiratory disease, cardiovascular disease, eye disease, metabolic disease in a mammal, including human, comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. Pharmaceutical composition for the treatment of symptoms selected from the group consisting of central nervous system diseases, liver / kidney diseases, genital health diseases, stomach diseases, skin diseases and cancer. Connective tissue disease, inflammatory disease, immune / allergic disease, infectious disease, respiratory disease, cardiovascular disease, eye disease, metabolic in said mammal comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal, including human A method of treating a condition selected from the group consisting of diseases, central nervous system diseases, liver / kidney diseases, genital health diseases, stomach diseases, skin diseases and cancer. A pharmaceutical composition for the treatment of symptoms that can be treated by inhibition of matrix metalloproteinases in a mammal, including humans, comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.